高频超声肝实质纹理特征定量联合血清AFP-L3水平评估乙型肝炎肝硬化患者肝功能分级价值研究*

目的 探讨应用高频超声肝实质纹理特征定量联合血清甲胎蛋白-L3(AFP-L3)水平评估乙型肝炎肝硬化患者肝功能分级的价值。方法 2019年6月～2021年5月我院诊治的乙型肝炎肝硬化患者87例和在本院进行体检的健康志愿者80例,将肝硬化患者依据肝功能分级分为A级、B级和C级。使用高频超声检查,获取肝实质纹理特征定量指标,包括缺陷图单位面积局部最大值(x D)、缺陷图均值(mean D)和缺陷图的熵(ε D)。采用ELISA法检测血清AFP-L3水平。应用MedCalc1 5.1统计学软件绘制受试者工作特征曲线(ROC),以曲线下面积(AUC)评价指标的评估价值。结果 肝硬化患者高频超声肝实质纹理特征定量指标x D、mean D、ε D和血清AFP-L3水平分别为(6.1±1.8)、(4.8±1.2)、(3.2±1.1)和(7.5±2.1)%,显著高于健康人【分别为(2.5±0.9)、(1.9±0.6)、(1.3±0.4)和(5.6±1.3)%,P<0.05】;24例Child C级患者x D、mean D、ε D和血清AFP-L3水平分别为(6.9±2.2)、(7.0±2.2)、(4.3±1.3)和(9.0±2.4)%,显著高于29例Child B级患者【分别为(6.5±1.7)、(5.4±1.5)、(3.8±1.1)和(7.9±2.1)%,P<0.05】或34例A级患者【分别为(5.3±1.3)、(3.2±1.0)、(2.1±0.6)和(6.1±1.5)%,P<0.05】;联合应用mean D、ε D和血清AFP-L3水平评估乙型肝炎肝硬化患者肝功能Child B级的AUC为0.910,其诊断的特异度为91.4%,显著高于各指标单独诊断(其特异度分别为70.7%、77.6%和75.9%,P<0.05)。结论 应用高频超声肝实质纹理特征定量联合血清AFP-L3水平评估乙型肝炎肝硬化患者肝功能分级有一定的价值,可为临床早期发现肝功能Child B级患者提供参考指标。     

Impaired splanchnic and peripheral glucose uptake in liver cirrhosis.

BACKGROUND/AIM: Patients with liver cirrhosis are insulin-resistant and frequently glucose-intolerant. Although peripheral glucose uptake has been shown to be impaired in liver cirrhosis, little is known about the significance of splanchnic (hepatic) glucose uptake after oral glucose load. METHODS/RESULTS: We performed an oral glucose tolerance test and euglycemic hyperinsulinemic clamp with oral glucose load for eight patients with liver cirrhosis and eight patients with chronic active hepatitis. The patients with liver cirrhosis had higher plasma glucose levels 2 h after glucose load than those with chronic active hepatitis (228+/-22 mg/dl vs. 102+/-9 mg/dl, p<0.01). Using the euglycemic hyperinsulinemic clamp with oral glucose load, we simultaneously measured peripheral and splanchnic glucose uptake. Peripheral glucose uptake in liver cirrhosis was 6.1+/-0.7 mg x kg(-1) x min(-1), which was lower than that in healthy volunteers (10.5+/-0.9 mg x kg(-1) x min(-1), p<0.05) and in chronic active hepatitis (8.4+/-0.3 mg x kg(-1) x min(-1), p<0.05). Furthermore, splanchnic glucose uptake in liver cirrhosis was much lower (20.1+/-3.4%) than in healthy volunteers (36.0+/-4.0%, p<0.05) and in chronic active hepatitis (37.2+/-3.1%, p<0.05). CONCLUSION: These results suggest that glucose intolerance in patients with liver cirrhosis is caused by a defect of the glucose uptake of both splanchnic and peripheral tissues.     

Short communication: interactions between nevirapine plasma levels,chronic hepatitis C,and the development of liver toxicity in HIV-infected patients

Both chronic hepatitis C and nevirapine (NVP) use are risk factors for transaminase elevation under highly active antiretroviral therapy. NVP is metabolized in the liver and its clearance could be altered in the presence of chronic hepatitis C virus (HCV) infection, enhancing the risk of liver toxicity. We examined NVP plasma levels in 70 HIV-infected subjects receiving NVP-containing triple combinations. The median (range) NVP plasma trough concentrations were similar in 32 HCV antibody-positive and 38 HCV antibody-negative patients (5.8 [0.7-29] vs. 6.1 [0.9-9.6] microg/ml). Thus, HCV coinfection itself does not seem to influence significantly the pharmacokinetics of NVP in HIV-infected subjects.     

Increased IGF-I : IGFBP-3 ratio in patients with hepatocellular carcinoma

BACKGROUND: The development of hepatocellular carcinoma in liver cirrhosis is associated with altered synthesis and secretion of several growth factors. AIM: The aim of this prospective study was to investigate the potential implication of IGF-I and its major binding protein (IGFBP-3) in the development of hepatocellular carcinoma. PATIENTS AND METHODS: IGF-I and IGFBP-3 were measured in 150 healthy subjects, 40 patients with liver cirrhosis and 63 with liver cirrhosis and untreated hepatocellular carcinoma. The ratio between IGF-I and IGFBP-3 was also calculated. RESULTS: Serum IGF-I (70 +/- 10 and 65 +/- 7 vs. 185 +/- 6.4 microg/l, P < 0.001) and IGFBP-3 levels (1225 +/- 113 and 984 +/- 67 vs. 3017 +/ -80 microg/l, P < 0.001) were lower in patients with liver cirrhosis, without or with hepatocellular carcinoma, than in controls. Age was negatively correlated with IGF-I levels in patients with liver cirrhosis (r = -0.6; P = 0.0002) as well as in controls (r = -0.8, P < 0.0001), but not in patients with hepatocellular carcinoma (r = -0.2; P = 0.2). Additionally, in patients with liver cirrhosis (r = -0.54; P = 0.0003) and more weakly in those with hepatocellular carcinoma (r = -0.24; P = 0.04) IGF-I levels were negatively correlated with liver failure measured according with Child class. Despite patients with class C hepatocellular carcinoma being older than those in the same functional class with cirrhosis (64 +/- 2 vs. 57 +/- 12 years, P < 0.01), they had a significantly increased IGF-I : IGFBP-3 ratio (0.18 +/- 0.05 vs. 0.41 +/- 0.09, P = 0.04), due mostly to increased IGF-I levels (27.1 +/- 5.6 vs. 42 +/- 6.2 microg/l) as IGFBP-3 levels were similar to patients with cirrhosis (734 +/- 81 vs. 679 +/- 83 microg/l). CONCLUSIONS: Hepatocellular carcinoma is associated with a higher IGF-I : IGFBP-3 ratio than that found in patients with liver cirrhosis and a similar degree of liver failure.     

Serum thioredoxin levels as an indicator of oxidative stress in patients with hepatitis C virus infection

BACKGROUND/AIM: It has recently been suggested that oxidative stress may be associated with hepatitis C virus (HCV) infection. Thioredoxin (TRX) is a stress-inducible thiol-containing protein. The aim of this study was to evaluate the clinical significance of serum TRX levels in patients with HCV-related chronic liver diseases. METHODS: Serum TRX levels were determined with a sandwich enzyme-linked immunosorbent assay kit in 174 serum HCV-RNA positive patients, including 6 asymptomatic carriers, 124 chronic hepatitis, 20 liver cirrhosis, and 24 hepatocellular carcinoma, and in 15 healthy volunteers. RESULTS: The serum TRX levels (medians and [ranges], ng/ml) were significantly elevated in the HCV-infected patients; 30.9 [20.7-37.7] in asymptomatic carriers, 34.5 [8.6-135.6]* in chronic hepatitis, 42.5 [21.4-97.2]* in liver cirrhosis, and 43.9 [11.7-180.3]** in hepatocellular carcinoma (*p<0.05, **p<0.001, vs. 24.9 [1.3-50.7] in healthy controls). Serum TRX levels were significantly correlated with the serum levels of ferritin and fibrogenesis markers, and with the histological stage of hepatic fibrosis. The serum TRX levels before interferon treatment of patients whose serum HCV-RNA was still positive on day 14 following interferon treatment (42.6 [20.1-90.0]) were significantly higher than those of patients whose serum HCV-RNA was negative on day 14 following interferon treatment (25.8 [7.4-59.8], p<0.05). CONCLUSIONS: The serum TRX levels of patients with HCV infection increased with their serum ferritin levels and the progression of liver fibrosis. Patients with higher serum TRX levels exhibited resistance to interferon therapy. Oxidative stress may therefore be responsible for the pathological mechanism of HCV-related liver diseases and be one of the impediments to eradication of HCV during interferon treatment.     

Digitoxin in patients with hepatorenal insufficiency after repeated oral administration

Following chronic oral administration of digitoxin 0.1 mg day-1 the pharmacokinetics of this glycoside were studied in seven patients with hepatorenal insufficiency and were compared with those of seven healthy volunteers. Liver cirrhosis of the patients was confirmed by liver biopsy. Mean creatinine clearance of the healthy subjects was 129.7 +/- 3.3 ml min-1 (mean +/- SEM), that of the patients was 25.6 +/- 20.4 ml min-1. Mean antipyrine clearance (parameter of oxidative liver function) was 49.7 +/- 6.0 ml min-1 in the volunteers and 22.0 +/- 2.9 ml min-1 in the patients. Plasma protein binding of digitoxin (PPB) was 95.0 +/- 1.1% in the patients and 96.7 +/- 0.6% in the healthy subjects (n.s.). Total body clearance of digitoxin (Cltot) was 0.0728 +/- 0.0120 ml min-1 kg-1 in the patients and 0.0615 +/- 0.0027 ml min-1 kg-1 in normals (n.s.]. Mean steady state plasma levels (Css) of the patients were 18.3 +/- 4.7 ng ml-1 and 15.8 +/- 1.3 ng ml-1 in the normals (n.s.). Our data obtained from chronic oral administration do not indicate a reduced total body clearance of digitoxin in patients with hepatorenal insufficiency.     

Plasma and platelet serotonin levels in patients with liver cirrhosis

AIM： To analyze the relationship between plasma and platelet serotonin levels and the degree of liver insufficiency. METHODS： The prospective study included 30 patients with liver cirrhosis and 30 healthy controls. The degree of liver failure was assessed according to the Child-Pugh classification. Platelet and platelet poor plasma serotonin levels were determined. RESULTS： The mean plasma serotonin level was higher in liver cirrhosis patients than in healthy subjects （215.0 ±26.1 vs 63.1 ± 18.1 nmol/L; P 〈 0.0001）. The mean platelet serotonin content was not significantly different in patients with liver cirrhosis compared with healthy individuals （4.8 ± 0.6; 4.2± 0.3 nmol/platelet; P 〉 0.05）. Plasma serotonin levels were significantly higher in ChildPugh grade A/B than in grade C patients （246.8 ± 35.0 vs 132.3 ± 30.7 nmol/L; P 〈 0.05）. However, platelet serotonin content was not significantly different between Child-Pugh grade C and grade A/B （4.6 ± 0.7 vs 5.2 ± 0.8 nmol/platelet; P 〉 0.05）. CONCLUSION： Plasma serotonin levels are significantly higher in patients with cirrhosis than in the controls and represent the degree of liver insufficiency. In addition, platelet poor plasma serotonin estimation is a better marker for liver insufficiency than platelet serotonin content.     

Lack of sex effect on the pharmacokinetics of primaquine

The pharmacokinetics of primaquine have been well defined in male volunteers, but there is little data on the disposition of the drug in women. We compared the kinetics of primaquine in nine male and nine female healthy Australian volunteers after the administration of a single oral dose (30 mg base) of primaquine. No statistical differences were observed in the following kinetic parameters of primaquine between men and women, respectively: maximum plasma concentration (93 +/- 26 and 115 +/- 38 ng/mL; 95% confidence interval [CI] of the mean difference: -55 to 10 ng/mL; P = 0.16), area under the curve (1.1 +/- 0.5 and 1.2 +/- 0.4 microg x h/mL; 95% CI: -0.6 to 0.3 microg x h/mL; P = 0.54), and clearance (0.34 +/- 0.12 and 0.39 +/- 0.14 L/h/kg; 95% CI: -0.17 to 0.08 L/h/kg; P = 0.46). The clinical relevance of such findings would suggest that sex does not have to be taken into account as a factor when prescribing primaquine for radical cure or terminal prophylaxis of Plasmodium vivax malaria.     

Reduced ubiquinone plasma levels in patients with liver cirrhosis and in chronic alcoholics

Ubiquinone (CoQ₁₀ coenzyme) is part of the respiratory chain in mitochondria, and acts as a scavenger in oxidative stress in cell membranes. Ubiquinone is mainly synthesized in the liver and partly derived from the diet; its plasma levels significantly correlate with tissue levels in experimental animals and in pathological states in man. By means of an original high-performance liquid chromatography technique, we measured ubiquinone plasma levels in 10 healthy subjects, in 27 patients with cirrhosis and in 22 chronic alcoholics with normal liver function. Ubiquinone levels were markedly reduced in cirrhosis (0.25 [SD 0.21] μg/ml vs. 0.92 [0.38] in controls; P<0.001), without any difference between alcohol- and non-alcohol-related disease. Also, in chronic alcoholics ubiquinone levels were nearly halved (0.49 [0.24]). In cirrhosis, ubiquinone plasma levels significantly correlated with cholesterol (P<0.05), and with total bilirubin levels (P<0.01). Our study highlights a remarkable deficiency in ubiquinone levels in patients with cirrhosis and in chronic alcoholics, to which both reduced hepatic synthesis and nutritional defects may contribute.     

Pharmacokinetics of roxatidine acetate in patients with chronic liver disease

BACKGROUND AND AIM: Patients with liver disease are prone to develop peptic ulceration and often receive H(2)-receptor antagonists. Therefore, it is important to clarify whether the pharmacokinetics of H(2)-receptor antagonists is affected by hepatic function. However, pharmacokinetics of a new H(2)-receptor antagonist, roxatidine acetate, in chronic liver disease has not been well known. In this study, we analyzed the pharmacokinetics of roxatidine in patients with liver disease. METHODS: Blood samples were obtained from 11 patients with chronic hepatitis, 11 patients with cirrhosis and six healthy subjects. Under fasting conditions, 75 mg of roxatidine acetate was administered orally, and plasma roxatidine levels were determined sequentially from 3 to 12 h. Relationships between pharmacokinetic variables and each parameter related to hepatic functions were also investigated. RESULTS: There was no difference in the pharmacokinetic variables and serum levels of roxatidine between chronic hepatitis and healthy controls. In contrast, in cirrhosis, serum roxatidine levels were significantly higher than those in chronic hepatitis and normal control. Half-life, the area under the plasma concentration-time curve and clearance in cirrhosis were also significantly longer, bigger and smaller than those in chronic hepatitis and healthy controls, respectively. The half-life became longer and the clearance became smaller in parallel with the progression of liver disease. Serum levels of hyaluronate and gamma-glutamyl transpeptidase showed a good correlation with half-life, clearance and elimination rate. A good correlation between creatinine clearance and elimination rate was found. CONCLUSION: Pharmacokinetics of roxatidine acetate is affected by hepatic function, and the dosage of roxatidine acetate for patients with liver disease, especially cirrhosis, should be modified.     

Elevated nitric oxide and 3′,5′ cyclic guanosine monophosphate levels in patients with alcoholic cirrhosis

AIM： To evaluate whether serum levels of nitric oxide （NO^.） and plasma levels of cyclic guanosine monophosphate （cGMP） and total glutathione （GSH） are altered in patients with alcoholic cirrhosis and to examine their correlation with the severity of liver disease.
METHODS： Twenty-six patients with alcoholic liver cirrhosis were studied. Serum levels of NO^. and plasma levels of cGMP and GSH were measured in 7 patients with compensated alcoholic cirrhosis （Child-Pugh A） and 19 patients with advanced cirrhosis （Child-Pugh B and C）. The model for end-stage liver disease （MELD） score was evaluated. Sixteen healthy volunteers served as controls. Liver enzymes and creatinine levels were also tested.
RESULTS： NO^. and cGMP levels were higher in patients with Child-Pugh B and C cirrhosis than in Child-Pugh A cirrhosis or controls （NO^.： 21.70 ± 8.07 vs 11.70 ± 2.74; 21.70± 8.07 vs 7.26 ± 2.47 μmol/L, respectively; P 〈 0.001） and （cGMP： 20.12 ± 6.62 vs 10.14 ± 2.78; 20.12 ± 6.62 vs 4.95 ± 1.21 pmol/L, respectively; P 〈 0.001）. Total glutathione levels were lower in patients with Child-Pugh B and C cirrhosis than in patients with Child-Pugh A cirrhosis or controls （16.04 ± 6.06 vs 23.01 ± 4.38 or 16.04 ± 6.06 vs 66.57 ±26.23 μmol/L, respectively; P 〈 0.001）. There was a significant correlation between NO^. and cGMP levels in all patients with alcoholic cirrhosis. A significant negative correlation between reduced glutathione/glutathione disulfide and the MELD score was found in all cirrhotic patients.
CONCLUSION： Our results suggest a role for oxidative stress in alcoholic liver cirrhosis, which is more significant in decompensated patients with higher levels of NO^. and cGMP and lower GSH levels than in compensated and control patients. Altered mediator levels in decompensated patients may influence the hemodynamic changes in and progression of liver disease.     

血红素氧合酶-一氧化碳系统对肝硬化大鼠血流动力学的影响

目的 观察血红素氧合酶-一氧化碳系统对肝硬化大鼠全身血流动力学的影响.方法将30只雄性SD大鼠分为对照组(14只)和肝硬化组(16只),肝硬化组大鼠皮下注射50%四氯化碳(以橄榄油稀释,0.003 ml/g),对照组给予相同剂量的橄榄油.12周后,将肝硬化组大鼠分为肝硬化给药组(8只)、肝硬化模型组(8只),对照组大鼠分为正常给药组(7只)、正常对照组(7只).肝硬化给药组和正常给药组大鼠经后颈部皮下注射锌原卟啉(20 μmol/kg),肝硬化模型组和正常对照组予以等渗盐水,用动脉插管生理多导仪记录心率、平均动脉压的变化,门静脉插管测定门静脉压,联二亚硫酸盐还原法测定血浆一氧化碳水平,用比色法测定胆红素生成量.数据间比较用t检验.结果 正常对照组与肝硬化模型组大鼠平均动脉压分别为(18.9±0.9)kPa和(15.6±1.7)kPa,门静脉压分别为(8.8±0.3)cm H2O(1 cm H2O=0.098 kPa)和(16.7±0.8)cm H2O,血浆一氧化碳分别为(10.4±1.3)μmol/L和(18.0±1.9)μmol/L,脾脏血红素氧合酶(HO)活性分别为(6.5±0.9)nmol·mg1·h1和(11.1±0.9)nmol·mg 1·h-1,小肠HO活性分别为(1.3±0.2)nmol·mg1·h-1和(2.5±0.1)nmo1·mg-1·h-1,两组比较,t值分别为4.52、23.10、8.42、9.28、15.10,P值均＜0.01,差异有统计学意义.正常对照组与肝硬化模型组大鼠肝脏HO活性分别为(2.7±0.2)nmol·mg-1·h-1、(2.7±0.1)nmol·mg-1·h-1,差异无统计学意义.肝硬化模型组、肝硬化给药组平均动脉压分别为(15.6±1.7)kPa、(17.3±1.5)kPa,两组比较,t=2.18,P＜0.05,差异有统计学意义,门静脉压分别为(16.7±0.8)cmH2O、(13.2±0.7)cmH2O,两组比较,t=8.53,P＜0.01,差异有统计学意义.结论 HO-CO系统的激活可能是肝硬化血流动力紊乱的重要原因.

Abstract：

Objective To investigate the role of heme oxygenase(HO), a catalyzing enzyme of heme to produce CO, in modulation of systemic circulation in CCl4-induced cirrhotic rats. Methods Saline (vehicle) and ZnPP were s.c. injected into the posterior necks of rats respectively and the rats were then anesthetized by pentobarbital sodium in four hours. Mean arterial pressure (MAP, kPa), heart rate (HR, b/min) and portal pressure (PP, cm/H2O) were measured by indwelling catheter. Plasma CO was determined by Chalmers method. Heme oxygenase acivity was determined by the rate of bilirubin formation. Results The cirrhotic rats showed significant hyperdynamic circulation indicated by decreased mean arterial pressure [MAP,(15.6 ± 1.7) vs (18.9 ± 0.9) kPa, t = 4.52, P ＜ 0.01] and increased portal pressure [PP, (16.7 ± 0.8)vs (8.8 ± 0.3) cm H2O, t = 23.10, P ＜ 0.01] as compared to normal control rats(NS). ZnPP could cause a significant increase in MAP [(17.3 ± 1.5) vs (15.6 ± 1.7) kPa, t = 2.18, P ＜ 0.05] and significant decrease in PP [(13.2 ± 0.7) vs (16.7 ± 0.8) cm H2O, t = 8.53, P ＜ 0.01] in cirrhotic rats. The cirrhotic group presented a significant increase in plasma CO [(18.0 ± 1.9) vs (10.4 ± 1.3) μ mol/L, t = 8.42, P ＜ 0.01] and HO activity in the spleens [(11.1 ± 0.9) vs (6.5 ± 0.9) nmol bilirubin/mg protein/h, t = 9.28, P ＜ 0.01 ] and intestines [(2.5 ±0.1) vs. (1.3 ± 0.2) nmol bilirubin/mg protein/h, t = 15.1, P ＜ 0.01]. ZnPP could cause significant decreases in plasma CO and HO activity in liver, spleen and intestine of both control and cirrhotic rats. Conclusion HO-CO system activation may be an important reason for the hemodynamic disturbance of liver cirrhosis.     

Effect of preoperative interventions on outcome following liver resection in a rat model of cirrhosis

BACKGROUND/AIMS: High morbidity and mortality rates in cirrhotic patients undergoing resections for hepatocellular malignancies underscore the need for identifying a therapy that will decrease fibrosis or enhance hepatic regenerative activity in the perioperative period. Thus, in the present study, 104 carbon tetrachloride-induced cirrhotic rats received either saline (untreated cirrhotic controls) or one of the following agents that have been reported to decrease hepatic fibrosis or increase hepatic regeneration; pentoxifylline, ciprofloxacin or a traditional Chinese herbal remedy (TCHR). Twelve additional rats served as healthy, non-cirrhotic controls. METHODS: Treatments were administered daily by gavage for 4 weeks followed by a 70% partial hepatectomy. Hepatic fibrosis was documented at the time of surgery by computer-assisted quantitation of collagen content. Liver function and hepatic regenerative activity were documented 24 h post partial hepatectomy by serum bilirubin determinations and a combination of 3[H]-Thymidine incorporation into hepatic DNA and proliferating cell nuclear antigen (PCNA) quantitation, respectively. RESULTS: Compared to untreated cirrhotic controls (8.1 +/- 0.7%), fibrosis was significantly reduced in the pentoxifylline- and ciprofloxacin-treated groups (4.6 +/- 0.2%, p<0.005 and 5.5 +/- 0.6%, p<0.05) but unchanged in the TCHR-treated group (6.6 +/- 11.0%). Post-operatively, total serum bilirubin levels were lower in the pentoxifylline (1.40 +/- 0.15 mg/dl,p<0.01) and ciprofloxacin (1.87 +/- 0.25 mg/dl, p<0.05)-treated groups, but unchanged in the TCHR group (2.20 +/- 0.45 mg/dl), when compared to untreated cirrhotic controls (3.00 +/- 0.37 mg/dl). Hepatic regenerative activity was also significantly improved in the pentoxifylline-treated group (17.8 +/- 2.2 versus 9.9 +/- 1.9 DPM/microg DNA in untreated cirrhotic controls, p<0.05), but unchanged in the ciprofloxacin (16.1 +/- 1.8 DPM/microg DNA) and TCHR (10.9 +/- 1.2 DPM/microg DNA)-treated groups. PCNA protein determinations were in keeping with the 3[H]-Thymidine results CONCLUSIONS: Pre-operative pentoxifylline holds promise as a useful therapeutic intervention for patients with cirrhosis requiring hepatic resection.     

Elevated urokinase-type plasminogen activator plasma levels are associated with deterioration of liver function but not with hepatocellular carcinoma

We measured urokinase-type plasminogen activator (u-PA) plasma levels in patients with various chronic liver diseases, including hepatocellular carcinoma (HCC), also measuring these levels in healthy volunteers. Plasma u-PA levels in the group of patients with decompensated liver cirrhosis (mean modified Pugh score of 14 points) were markedly elevated and significantly higher than those in the patients with decompensated liver cirrhosis with HCC (modified Pugh score of 10 points), those with compensated liver cirrhosis with HCC, and those with compensated liver cirrhosis. Patients in all these three latter groups had moderately and significantly elevated u-PA levels compared to levels in the chronic hepatitis group and the healthy volunteers, but the levels were not significantly different from each other. There was no relationship between u-PA plasma level and the type of HCC tumor invasion or number or size of tumors. Significant correlations were found between u-PA plasma levels and the results of seven different liver function tests in three groups without associated HCC; u-PA antigen and prothrombin time (%), hepaplastin test (%), serum cholinesterase, serum albumin, serum total cholesterol, and indocyanine green clearance correlated negatively, while u-PA antigen and serum total bilirubin correlated positively. These results suggest that plasma u-PA is associated with deterioration of liver function but not with HCC invasion.     

Central serotoninergic response to orthostatic challenge in patients with neurocardiogenic syncope.

AIMS: To determine whether central serotoninergic system activity is impaired by orthostatic challenge in patients with neurocardiogenic syncope (NCS). METHODS AND RESULTS: Thirty-five [mean age: 24 (SD): 6 years] patients with a clinical history of NCS and positive head-up tilt test and 35 age-matched healthy volunteers (CON = 25+/-5 years) with negative response were studied. Overnight dexamethasone suppression test (DST) (1.5 mg given at 11 p.m.) was performed to assess the sensitivity of the hypothalamic-pituitary-adrenal axis by measuring next day cortisol (microg/dL) at 8 a.m. and 4 p.m. Cardiac autonomic function, cortisol, and prolactin (ng/dL) were also determined at baseline supine (BAS) and after 5, 10, and 15 min of orthostatic stress (OS) at 60 degrees . No significant differences were observed in cortisol plasma levels after the DST: CON = 0.6+/-0.6 microg/dL vs. NCS = 0.6+/-0.5; P = 0.7. Cardiac autonomic function, cortisol, and prolactin responses were similar in both study groups (CON vs. NCS; P > 0.05) during BAS: cortisol = 8.6+/-4 vs.8.7+/-4 microg/dL and prolactin = 16.8+/-9 vs. 16.8+/-9 ng/dL; OS-5: cortisol = 8.7+/-5 vs. 8.5+/-4 microg/dL and prolactin = 16.9+/-9 vs. 15.8+/-9 ng/dL; OS-10: cortisol = 8.5+/-5 vs. 8.1+/-3 microg/dL; prolactin = 16.2+/-9 vs. 15.8+/-9 ng/dL, and OS-15: cortisol = 9.0+/-5 vs. 8.4+/-4 microg/dL; prolactin = 17.1+/-9 vs. 15.5+/-9 ng/dL. CONCLUSION: Central serotoninergic response during orthostatic challenge was not impaired in patients with recurrent NCS. These findings suggest that the activation of the hypothalamic-pituitary-adrenal axis is not altered in patients with recurrent NCS.     

肝硬化患者尿激酶型纤溶酶原激活物及其受体测定的临床意义

目的检测肝硬化患者血浆中尿激酶型纤溶酶原激活物(u-PA)及其受体(u-PAR)的含量,分析代偿期和失代偿期肝硬化患者纤溶活化的变化情况。方法 ELISA法检测48例肝硬化和30名健康志愿者的血浆中u-PA及其受体的含量。结果失代偿期肝硬化患者u-PA(1362±481ng.l~(-1))及u-PAR(1037±357ng.l~(-1))均明显高于对照(P<0.05,P<0.05),且u-PA高于代偿期肝硬化患者(P<0.05)结论肝硬化患者存在明显的纤溶活性增强,并随病情的加重而增加。     

Platelet function rather than plasmatic coagulation explains hypercoagulable state in cholestatic liver disease

BACKGROUND/AIMS: As compared to other chronic liver diseases, cholestatic disorders are associated with a better outcome of variceal bleeding and less blood loss at transplantation, suggesting the presence of a hypercoagulable state. We have assessed plasmatic coagulation and platelet function in patients with cholestatic and non-cholestatic liver disease. METHODS: Thirty-seven patients with chronic cholestatic liver disease (primary biliary cirrhosis (PBC)/primary sclerosing cholangitis (PSC)), 53 patients with chronic hepatitis C (HCV) or alcoholic cirrhosis (C2), and 62 healthy controls were studied. RESULTS: Thrombelastography revealed a hypercoagulable state in non-cirrhotic patients with PBC/PSC, but not in those with HCV (ma-value: 6.54[6.25-6.92, 95%CI] vs. 5.39[5.11-5.58], P < 0.05) possibly due to higher fibrinogen levels in PBC/PSC patients (369[329-418]mg/dl vs. 263[250-275]mg/dl, P < 0.05). PFA-100 closure time was prolonged in HCV/C2 patients with advanced cirrhosis, but not in cirrhotic patients with PBC/PSC (Child B; epinephrine stimulation: 192[161-229]s vs. 132[105-158]s, P < 0.05). Flow cytometric studies of platelet receptors and granules revealed a higher surface expression of CD42b (112[105-119]% vs. 100[95-104]%, P < 0.05) and LIBS-1 (261[184-348]% vs. 121[92-145]%, P < 0.05) in patients with PBC/PSC than in those with HCV/C2. CONCLUSIONS: These results indicate that platelet function differs between patients with cholestatic and non-cholestatic liver disease and is stable or even hyperactive in patients with PBC and PSC.     

Steady-state plasma and intrapulmonary concentrations of levofloxacin and ciprofloxacin in healthy adult subjects

STUDY OBJECTIVE: To determine the steady-state plasma, epithelial lining fluid (ELF), and alveolar macrophage (AM) concentrations of levofloxacin and ciprofloxacin. DESIGN: Multiple-dose, open-label, randomized pharmacokinetic study. PARTICIPANTS: Thirty-six healthy, nonsmoking adult subjects were randomized either to oral levofloxacin, 500 or 750 mg once daily for five doses, or ciprofloxacin, 500 mg q12h for nine doses. INTERVENTIONS: Venipuncture, bronchoscopy, and BAL were performed in each subject at 4 h, 12 h, or 24 h after the last administered dose of antibiotic. MEASUREMENT AND RESULTS: Mean plasma concentrations of levofloxacin and ciprofloxacin were similar to those previously reported. For once-daily dosing of levofloxacin, 500 mg, the mean (+/- SD) steady-state concentrations at 4 h, 12 h, and 24 h in ELF were 9.9 +/- 2.7 microg/mL, 6.5 +/- 2.5 microg/mL, and 0.7 +/- 0.4 microg/mL, respectively; AM concentrations were 97.9 +/- 80.0 microg/mL, 36.7 +/- 23.4 microg/mL, and 13.8 +/- 16.0 microg/mL, respectively. For levofloxacin, 750 mg, the mean steady-state concentrations in ELF were 22.1 +/- 14.9 microg/mL, 9.2 +/- 5.3 microg/mL, and 1.5 +/- 0.8 microg/mL, respectively; AM concentrations were 105.1 +/- 65.5 microg/mL, 36.2 +/- 26.1 microg/mL, and 15.1 +/- 2.0 microg/mL, respectively. The concentrations of ciprofloxacin at 4 h and 12 h in ELF were 1.9 +/- 0.9 microg/mL and 0.4 +/- 0.1 microg/mL, respectively; AM concentrations were 34.9 +/- 23.2 microg/mL and 6.8 +/- 5.9 microg/mL, respectively. The differences in the ELF concentrations of the two levofloxacin groups vs those of the ciprofloxacin group were significant (p < 0.05) at each sampling time. CONCLUSIONS: Levofloxacin was more extensively distributed into intrapulmonary compartments than ciprofloxacin and achieved significantly higher steady-state concentrations in plasma and ELF during the 24 h after drug administration.     

Concentrations of carcinoembryonic antigen in serum and bronchoalveolar lavage fluid of asthmatic patients with mucoid impaction]

BACKGROUND: Concentration of carcinoembryonic antigen (CEA) is known as a marker of malignant transformation and chronic inflammation. We recently observed increased levels of serum CEA in a patient with asthma accompanied by mucoid impactions, which dramatically decreased after a sequence of bronchial washings. The present study evaluated relationships between levels of CEA, bronchial asthma and mucoid impactions. METHODS: Serum CEA concentrations were determined by chemiluminescent immunoassay (CLIA) or enzyme immunoassay in 44 subjects, comprising 9 asthmatic patients with mucoid impactions, 13 asthmatic patients without mucoid impactions, 12 patients with bronchiectasis, and 10 healthy volunteers. CEA concentrations in bronchoalveolar lavage fluid (BALF) were determined in 5 asthmatic patients with mucoid impactions and 10 healthy volunteers. RESULTS: Serum concentrations of CEA were significantly increased in asthmatic patients with mucoid impactions compared with patients without mucoid impactions, patients with bronchiectasis, or healthy volunteers (median [range], 17.3 ng/ml [2.8-28.8 ng/ml]; 3.0 ng/ml [1.5-7.1 ng/ml], 2.2 ng/ml [0.9-17.9 ng/ml], and 1.9 ng/ml [0.6-2.9 ng/ml], respectively). Concentrations of CEA in BALF were also significantly increased in asthmatic patients with mucoid impactions compared to healthy volunteers (3.2 ng/ml albumin [1.2-12.4 ng/ml albumin] vs. 0.4 ng/ml albumin [0.2-1.9 ng/ml albumin]). CONCLUSION: These findings suggest that bronchial asthma with mucoid impactions is among several pathogeneses that cause increased levels of CEA in serum and BALF.     

Comparative effects of pioglitazone, glibenclamide, and voglibose on urinary endothelin-1 and albumin excretion in diabetes patients

Urinary endothelin (ET)-1 excretion is present in non-insulin dependent diabetes (NIDDM) patients with microalbuminuria, and an increase in circulating ET-1 precedes the microalbuminuric phase of renal injury related to diabetes. The aim of the present study was to determine whether various drugs alter urinary ET-1 levels and urinary albumin excretion (UAE) in NIDDM patients with microalbuminuria. Forty-five NIDDM patients with microalbuminuria were randomly assigned to three groups: those treated with pioglitazone at 30 mg/day (n=15), those treated with glibenclamide at 5 mg/day (n=15), and those treated with voglibose at 0.6 mg/day (n=15). Patients received these drugs for 3 months. UAE, urinary ET-1, and plasma ET-1 levels were measured in these patients before and after treatment. Before treatment, UAE, urinary ET-1, and plasma ET-1 levels differed little among the three groups. UAE in the 45 NIDDM patients (156.2+/-42.8 microg/min) was greater than that in 30 healthy controls (8.2+/-2.6 microg/min) (P<.001). Urinary ET-1 levels in the NIDDM patients (8.7+/-1.3 ng/g urinary creatinine (UC)) were significantly higher than that in the controls (2.4+/-0.2 ng/g UC) (P<.01). Plasma ET-1 levels, however, in the NIDDM patients (1.3+/-0.4 pg/ml) did not differ significantly from the levels in healthy controls (1.0+/-0.6 pg/ml). Pioglitazone but no glibenclamide or voglibose reduced UAE from 142.8+/-42.2 to 48. 4+/-18.2 microg/min (P<.01) and urinary ET-1 levels from 8.6+/-1.3 to 3.4+/-0.5 ng/g UC (P<.01). These data suggest pioglitazone to be effective in reducing UAE and urinary ET-1 concentrations in NIDDM patients with microalbuminuria.