Vasoactive factors and hemodynamic mechanisms in the pathophysiology of portal hypertension in cirrhosis

Portal hypertension is primarily caused by the increase in resistance to portal outflow and secondly by an increase in splanchnic blood flow, which worsens and maintains the increased portal pressure. Increased portal inflow plays a role in the hyperdynamic circulatory syndrome, a characteristic feature of portal hypertensive patients. Almost all the known vasoactive systems/substances are activated in portal hypertension, but most authors stress the pathogenetic role of endothelial factors, such as COX-derivatives, nitric oxide, carbon monoxide. Endothelial dysfunction is differentially involved in different vascular beds and consists in alteration in response both to vasodilators and to vasoconstrictors. Understanding the pathogenesis of portal hypertension could be of great utility in preventing and curing the complications of portal hypertension, such as esophageal varices, hepatic encephalopathy, ascites.     

发酵乳对肝硬化失代偿期患者肠黏膜屏障功能的影响

观察发酵乳在改善肝硬化失代偿期患者肠黏膜屏障功能、肝功能及提高患者生活质量方面的作用。

选择我院78例确诊为肝硬化失代偿期的患者,随机分成对照组和发酵乳组,其中对照组42例,发酵乳组36例。对照组患者给予常规综合治疗,发酵乳组在常规综合治疗的基础上给予口服发酵乳治疗,在治疗前及治疗4周后分别检测并比较两组患者肠黏膜屏障功能、血清白蛋白、血浆氨水平及慢性肝病问卷评分（CLDQ）的变化。

治疗前两组患者肠屏障功能、血清白蛋白、氨水平及CLDQ评分差异无统计学意义（均P＞0.05）。治疗4周后,发酵乳组患者血清内毒素、血清二胺氧化酶、D-乳酸及血浆氨水平较治疗前显著降低,较对照组治疗后亦降低（均P＜0.05）。发酵乳组患者血清白蛋白水平及部分CLDQ评分较治疗前显著升高,较对照组治疗后亦升高（均P＜0.05）。

在常规综合治疗的基础上加用发酵乳可调节肝硬化失代偿期患者肠道菌群,改善肠黏膜屏障功能,从而保护肝脏功能,提高患者生活质量。

     

Substrate turnover and oxidation during moderate-intensity exercise following acute plasma volume expansion.

In previous work using prolonged, light cycle exercise, we were unable to demonstrate an effect of acute plasma volume (PV) expansion on glucose kinetics or substrate oxidation, despite a decline in whole-body lipolysis (Phillips et al., 1997). However, PV is known to decrease arterial O2 content. The purpose of this study was to examine whether substrate turnover and oxidation would be altered with heavier exercise where the challenge to O2 delivery is increased. Eight untrained males (VO2max = 3.52 +/- 0.12 l/min) twice performed 90 min of cycle ergometry at 62 % VO2peak, both prior to (CON) and following induced plasma volume expansion (Dextran [6 %] or Pentaspan [10 %]) (6.7 ml/kg) (PVX). Glucose and glycerol kinetics were determined with primed constant infusions of [6.6-(2)H2] glucose and [(2)H5] glycerol, respectively. PVX resulted in a 15.8 +/- 2.2 % increase (p < 0.05) in PV. Glucose and glycerol appearance (Ra) and utilization (Rd), although increasing progressively (p < 0.05) with exercise, were not different between conditions. Similarly, no differences in substrate oxidation, either fat or carbohydrate, were observed between the two conditions. Prolonged exercise resulted in an increase (p < 0.05) in plasma glucagon and a decrease (p < 0.05) in plasma insulin during both conditions. With PVX, the exercise-induced increase in glucagon was diminished (p < 0.05). We conclude that impairment in O2 content mediated by an elevated PV does not alter glucose, and glycerol kinetics or substrate oxidation even at moderate exercise intensity.     

Significance of plasma skimming and plasma volume expansion.

The organs associated with plasma volume expansion, i.e., the red bone marrow, the enlarged spleen, and the uteroplacental complex, are arteriovenous shunts with an interposed sinusoidal stroma able to skim off plasma-rich blood. In the spleen, plasma separation is an integral part of the hemoconcentration. In the red bone marrow, plasma skimming might provide a washout mechanism for the many newly formed erythrocytes and platelets from the sinusoids to the peripheral blood circulation. In the uteroplacental complex, skimming of plasma-rich blood is beneficial in increasing blood flow in the myometrium, kidneys, and skeletal musculature. The hypervolemic status with anemia will simulate a negative iron balance, which speeds up the absorption of iron. Thus a conceptual unit seems to exist in which rheological factors influence such functions as transport of newly formed blood cells into the circulation (in the red bone marrow), hemoconcentration (in the spleen), and iron balance during pregnancy (in the uteroplacental complex).     

Ineffectiveness of acute scalp expansion.

The aim of this study was to test the ex vivo biomechanical properties of acutely expanded scalp flaps to quantitatively assess the efficacy of acute scalp expansion. A total of 14 fresh male cadavers were used for the study. In each cadaver, a rectangular (4 x 10 cm), laterally based flap was designed on each side of the scalp, starting from the superior margin of the external auditory canal. One randomly selected flap per scalp underwent acute intermittent expansion (a 3-minute expansion/3-minute rest cycle was performed three times with the maximum expansion achievable); the contralateral flap served as a control. After the expansion process, the acutely expanded flaps were measured to assess whether applied biomechanical stress caused any changes in flap dimensions. The biomechanical properties (stress/strain ratio, mean stiffness) of both expanded and control flaps were then assessed by means of a dynamometer and a force transducer. The obtained data showed that the biomechanical benefits provided by acute scalp expansion were not statistically different (p < 0.05) from those obtained by simple subgaleal undermining. No change of length nor gain in compliance was observed in the acutely expanded flaps as compared with control scalp flaps. In the authors' opinion, a possible explanation (to be further validated) for the lack of effect of acute scalp expansion might be that the inelastic galea aponeurotica did not allow mechanical creep to exploit the inherent elastic properties of the overlying scalp skin.     

枯草杆菌肠球菌二联活菌胶囊对肝硬化失代偿期患者的临床疗效

目的 观察枯草杆菌肠球菌二联活菌胶囊对肝硬化失代偿期患者的临床疗效。方法 选择2013年6月至2016年6月在湖北医药学院附属人民医院住院治疗的85例肝硬化失代偿期患者为研究对象,随机分为观察组（43例）和对照组（42例）。对照组患者接受肝硬化常规治疗,观察组在对照组基础上加用枯草杆菌肠球菌二联活菌胶囊500 mg/次,3次/d,口服。两组患者疗程均为2个月。观察并比较两组患者治疗前后肝肾功能指标[丙氨酸转氨酶（ALT）、总胆红素（TBil）、前白蛋白（PA）、血肌酐（sCr）、胱抑素C（CysC）、β2微球蛋白（β2-MG）]、肠黏膜屏障功能指标[血氨、内毒素、肿瘤坏死因子（TNF-α）、血清二胺氧化酶（DAO）]、Child-Pugh评分及并发症发生率。结果 治疗后观察组患者ALT、TBil、CysC、β2-MG水平显著下降,PA水平显著升高（P<0.05或P<0.01）,对照组患者治疗后ALT水平也明显下降（P<0.01）,且观察组患者ALT、CysC、β2-MG下降幅度较对照组更大（P<0.05或P<0.01）。两组患者血氨、内毒素、TNF-α和DAO水平较治疗前明显下降（P<0.01）,且观察组患者下降幅度较对照组更大（P<0.01）。观察组患者Child-Pugh评分显著降低（P<0.01）,且其下降幅度较对照组更大（P<0.05）。观察组患者并发症的发生率明显低于对照组（P＜0.05）。结论 枯草杆菌肠球菌二联活菌胶囊能有效改善肝硬化失代偿期患者的肝肾功能,修复肠黏膜屏障功能,降低血氨、内毒素、TNF-α和DAO水平,减少并发症的发生。     

Quantitative hepatic phosphorus-31 magnetic resonance spectroscopy in compensated and decompensated cirrhosis

Few studies have examined the physiological/biochemical status of hepatocytes in patients with compensated and decompensated cirrhosis in situ. Phosphorus-31 magnetic resonance spectroscopy ((31)P MRS) is a noninvasive technique that permits direct assessments of tissue bioenergetics and phospholipid metabolism. Quantitative (31)P MRS was employed to document differences in the hepatic metabolite concentrations among patients with compensated and decompensated cirrhosis as well as healthy controls. All MRS examinations were performed on a 1.5-T General Electric Signa whole body scanner. The concentration of hepatic phosphorylated metabolites among patients with compensated cirrhosis (n = 7) was similar to that among healthy controls (n = 8). However, patients with decompensated cirrhosis (n = 6) had significantly lower levels of hepatic ATP compared with patients with compensated cirrhosis and healthy controls (P < 0.02 and P < 0.009, respectively) and a higher phosphomonoester/phosphodiester ratio than controls (P < 0.003). The results of this study indicate that metabolic disturbances in hepatic energy and phospholipid metabolism exist in patients with decompensated cirrhosis that are not present in patients with compensated cirrhosis or healthy controls. These findings provide new insights into the pathophysiology of hepatic decompensation.     

Fluid and electrolyte hormonal responses to exercise and acute plasma volume expansion

Grant, S. M., H. J. Green, S. M. Phillips, D. L. Enns, andJ. R. Sutton. Fluid and electrolyte hormonal responses to exerciseand acute plasma volume expansion. J. Appl.Physiol. 81(6): 2386-2392, 1996.To investigatethe effect of acute graded increases in plasma volume (PV) on fluid andregulatory hormone levels, eight untrained men (peak aerobic power 45.2 ± 2.2 ml ^· kg^{1 ·} min¹)performed prolonged cycle exercise (46 ± 4% maximal aerobic poweron three occasions, namely, with no PV expansion (Con) and after 14%(Low) and 21% (High) expansions, respectively. The exercise plasmalevels of aldosterone (Aldo), arginine vasopressin (AVP), and atrialnatriuretic peptide (ANP) were all altered by acute PV increases. Apronounced blunting (P < 0.05) ofthe Aldo response during exercise was observed, the magnitude of whichwas directly related to the amount of hypervolemia (Con < Low < High). At 120 min of exercise, Aldo concentrations were 660 ± 71, 490 ± 85, and 365 ± 78 pg/ml for Con, Low, and High conditions,respectively. In contrast, the lower AVP and the higher ANP observedduring exercise appeared to be due to the effect of PV expansion onresting concentrations. Because osmolality did not vary amongconditions, the results indicate that PV represents an importantprimary stimulus in the response of Aldo to exercise. The lowerexercise blood concentrations of both epinephrine and norepinephrineobserved with PV expansion would suggest that a lower sympathetic drive may be implicated at least in the lower Aldo responses.

     

枯草杆菌肠球菌二联活菌胶囊对失代偿期肝硬化患者的保护作用

目的 探讨枯草杆菌肠球菌二联活菌胶囊对失代偿期肝硬化患者的保护作用。方法 125例失代偿期肝硬化患者被随机分为观察组（63例）和对照组（62例）。对照组接受肝硬化常规治疗,观察组在对照组基础上加用枯草杆菌肠球菌二联活菌胶囊500 mg/次,3次/d,口服。2组疗程均为2个月。观察两组患者治疗前后肝功能（ALT、TBil、PA）、血氨、血清内毒素、炎症反应因子（IL-6、TNF-α、CRP）、Child-Pugh分级变化及并发症发生情况。结果 治疗后观察组ALT、TBil、血氨、血清内毒素、IL-6、TNF-α及CRP明显降低,PA明显升高（P＜0.01）,对照组ALT、TBil、血氨、IL-6、TNF-α及CRP也明显降低（P＜0.05或P＜0.01）;两组治疗后比较,观察组上述指标的改善情况优于对照组（P＜0.01）;观察组Child-Pugh分级有明显改善（P0.05）;观察组并发症SBP、HE、HRS的发生率明显低于对照组（P＜0.05）。治疗过程中未发现明显不良反应。结论 枯草杆菌肠球菌二联活菌胶囊能降低失代偿期肝硬化患者的血氨、血清内毒素及炎症因子IL-6、TNF-α、CRP水平,改善肝功能,减少并发症的发生。     

Role of ascitic endocan levels in the diagnosis of spontaneous bacterial peritonitis in decompensated cirrhosis

Abstract

Objective: To assess the role of ascitic endocan levels in the diagnosis of spontaneous bacterial peritonitis (SBP) in decompensated cirrhosis.

Methods: Ascites samples, as well as demographic and laboratory data, were collected at admission from patients with decompensated cirrhosis. Ascitic endocan, tumour necrosis factor-α (TNF-α), and interleukin-6 (IL-6) levels were measured by ELISA. The influencing factors of SBP, the correlation of ascitic endocan with other inflammatory indicators, and the diagnostic value of ascitic endocan for SBP were analyzed.

Results: A total of 167 patients were enrolled, 39 with the SBP group and 128 in the non-SBP group. Ascitic endocan, TNF-α, and IL-6 levels were significantly higher in the SBP group than in the non-SBP group (p?<?0.001). Multivariate analysis demonstrated that ascitic endocan was an independent risk factor for SBP [OR = 1.006 (95% CI: 1.002–1.011); p?<?0.001]. Endocan was positively correlated with ascites polymorphonuclear leukocytes, TNF-α, and IL-6. ROC curve analysis showed that ascitic endocan had an AUC of 0.805 for the diagnosis of SBP (p?<?0.001) and had a sensitivity of 82.1% and specificity of 73.4% when the cut-off value was 295.011?pg/ml.

Conclusions: Ascitic endocan level is an independent risk factor and a valuable diagnostic indicator for SBP in decompensated cirrhosis.     

Effect of acute ethanol load on plasma immunoreactive insulin and glucagon.

The effect of a single large dose of ethanol (5 mg/kg body weight) on plasma glucagon (IRG) and insulin (IRI) concentrations was studied in rats fasting for 24 hr. Hepatic cAMP concentration and blood glucose were also estimated and correlated with hormonal changes. Plasma IRG concentrations had doubled by the first sampling time (2 hr) and remained at this level up to 16 hr after ethanol administration. Plasma IRI concentrations were not affected by ethanol. Hepatic cAMP concentrations reflected changes in the plasma insulin/glucagon ratio, which seems to be the major determining factor for hepatic cAMP even during ethanol oxidation. Hypoglycemia was not found in the ethanol group during the experimental period of 24 hr, and it was therefore concluded that ethanol may stimulate glucagon secretion in rats even without concurrent hypoglycemia. Possible mechanisms for the action of ethanol on the endocrine pancrease are discussed.     

Extreme elevation of serum alpha fetoprotein in decompensated cirrhosis without HCC: an ominous sign

Three cases of extreme elevation of serum alpha fetoprotein (>10,000 ng/mL) with decompensated cirrhosis without demonstrable hepatocellular carcinoma are reported. While 2 patients died of liver failure, 1 survived after liver transplantation. Extreme elevation of alpha fetoprotein not associated with hepatocellular carcinoma in liver cirrhosis heralds an ominous prognosis necessitating urgent liver transplantation.     

脐血干细胞移植治疗失代偿期肝硬化的临床疗效

目的:探讨人脐血干细胞(umbilical cord blood stem cell,UCBSC)外周静脉移植治疗失代偿期肝硬化的临床疗效及可行性.方法:20例失代偿期肝硬化患者采用人UCBSC外周静脉移植治疗,治疗后定期观察患者血清转氨酶(ALT、AST)、总胆红素(TBIL)、白蛋白(ALB)、凝血酶原时间(PT)和纤维蛋白原(FIB)水平变化,并观察患者临床症状及体征的改善情况及不良反应.结果:UCBSC移植治疗后2周,各项肝功能指标较治疗前无显著性差异(P＞0.05);治疗后4周,除ALT和AST有所改善外(P＜0.05),其余指标无明显改善;治疗后8周各项肝功能指标均有改善(P＜0.05),12周有显著性改善(P＜0.01).治疗后4周大多数患者的临床症状有明显改善,腹水减少和双下肢浮肿减轻15例(75.0%)、乏力好转16例(80%)、食欲改善13例(65%).UCBSC移植后12周患者总体生存率为90%,其中2例患者分别在UCBSC静脉移植后4周和8周因为肝性昏迷和自发性细菌性腹膜炎而死亡.所有患者均未发现与细胞移植相关的副作用.结论:UCBSC外周静脉移植是治疗失代偿期肝硬化一种安全有效的方法,短期内可以改善失代偿期肝硬化患者肝功能及临床症状,是一种值得推荐的治疗方法.     

Effect of acute exercise on plasma neurotensin levels

Neurotensin (NT) levels were examined in five aerobically untrained females aged 20-36 engaged in acute graded exercise testing. In addition to radioimmunoassay measurements, high pressure liquid chromatography was performed to further characterize plasma NT-like immunoreactivity (NTLI). Epinephrine (E), norepinephrine (NE), and lactate (L) responses were also determined. Exercise testing consisted of one hour of treadmill running subdivided into three 20-minute segments representing 50, 60, and 70%, respectively, of the previously determined maximal aerobic capacity. Mock testing established baseline values for each subject. Three components of NTLI were evaluated: NT(1-13), NT(1-8), and NT(1-11). Resting NT(1-13) concentrations averaged 5.8 +/- 4.2 fmol/ml, while mean NT(1-8) values were 13.0 +/- 5.2 fmol/ml, and NT(1-11) averaged 5.8 +/- 3.2 fmol/ml. Peak exercise values were: for NT(1-13), 5.4 +/- 2.0 fmol/ml, for NT(1-8), 13.5 +/- 2.8 fmol/ml, and for NT(1-11), 5.9 +/- 0.5 fmol/ml. Analysis of variance with repeated measures detected no changes in these levels with exercise. Four-fold increases in E (36 +/- 3 pg/ml to 121 +/- 51 pg/ml), NE (340 +/- 95 pg/ml to 1431 +/- 319 pg/ml), and L (0.8 +/- 0.1 mM to 4.3 +/- 1.7 mM) confirmed the stress of exercise on the body in general, and the sympatho-adrenal system in particular. While other research has associated peripheral NT metabolite elevations with stressful stimuli in laboratory animals, the results of the present study suggest either that NT is not released from the human adrenal medulla during exercise, or that peripheral sampling precludes detection of any increases in NT from the adrenal medulla with currently available radioimmunoassay systems.     

Endothelin-3 like immunoreactivity in plasma of patients with cirrhosis of the liver.

A highly specific and sensitive radioimmunoassay (RIA) has been established for determination of endothelin-3 like immunoreactivity in human plasma to investigate its possible role in hemodynamic alterations due to liver disease. Crossreactivity with other endothelin isoforms was always below 4 %, the lower detection limit following extraction on Sep-Pak C18 cartridges was 0.5 pg/ml. The concentration of endothelin-3 (mean +/- SEM) was 4.16 +/- 0.56 pg/ml (n = 13) in plasma of patients with cirrhosis of the liver, three fold higher than in age matched controls (1.35 +/- 0.27 pg/ml, n = 12, p less than 0.01). Plasma immunoreactivity was confirmed to be endothelin-3 related by reverse-phase HPLC. These data could suggest a role of plasma endothelin-3 in circulatory changes, as they occur in cirrhosis of the liver.