Pharmacologic therapy of portal hypertension

Portal hypertension is a progressively debilitating complication of cirrhosis and a principal cause of mortality in patients who have hepatic decompensation. During the last few decades, significant clinical advances in the prevention of initial variceal hemorrhage, the management of acute variceal hemorrhage, and the prevention of recurrent variceal hemorrhage have reduced the morbidity and mortality of this lethal complication of cirrhosis. This article discusses the pharmacologic treatment of portal hypertension, including preprimary prophylaxis, prevention of a first variceal hemorrhage, treatment of acute variceal hemorrhage, and secondary prophylaxis of a variceal hemorrhage.     

Management of portal hypertension after variceal hemorrhage

Each variceal bleed is associated with 20% to 30% risk of dying. Management of portal hypertension after a bleed consists of (1) control of bleeding and (2) prevention of rebleeding. Effective control of bleeding can be achieved either pharmacologically by administering somatostatin or octreotide or endoscopically via sclerotherapy or variceal band ligation. In practice, both pharmacologic and endoscopic therapy are used concomitantly. Rebleeding can be prevented by endoscopic obliteration of varices. In this setting, variceal ligation is the preferred endoscopic modality. B-blockade is as effective as endoscopic therapy and, in combination, the two modalities may be additive.     

Pharmacologic therapy for portal hypertension

Pharmacologic therapy for portal hypertension is effective in the treatment and prevention of hemorrhage from esophagogastric varices. Acute hemorrhage from varices can be treated with intravenous agents such as somatostatin or terlipressin, either alone or in combination with endoscopic sclerotherapy or band ligation. Intravenous octreotide has not shown effectiveness as monotherapy, but it appears to be beneficial when combined with endoscopic treatment. The prevention of rebleeding after initial hemorrhage is best accomplished with non-selective beta blockers, endoscopic band ligation of varices, or a combination of endoscopic and pharmacologic therapies. The addition of oral nitrates may further decrease rebleeding rates, but more data from randomized trials are needed. Beta blockers are currently the only agents recommended for the primary prevention of variceal hemorrhage.     

PTVE对门脉高压症食管胃底曲张血管破裂出血的疗效

目的 探讨经皮穿肝曲张血管栓塞术（PTVE）对门静脉压力、门静脉血流量的影响及食管胃底曲张静脉出血、止血、延长再出血间期的价值。方法 36例食管胃底曲张静脉破裂大出血患者行PTVE治疗,术中测门静脉压力。术前、术后彩色多普勒测门静脉血流量。另选择35例药物治疗患者作为对照组。结果 PTVE组成功率94．87％。活动性出血全部成功止血;曲张血管栓塞后与栓塞前比较,门静脉压力明显升高（P〈0．05）．门静脉血流量变化不明显（P〉0．05）。术后PTVE组、对照组分别平均随访420．36、250．56d．再出血率分别为10％、42．86％．半数再出血时间分别为430、131d;两组再出血率、半数再出血时间比较有统计学意义（P〈0．01）。结论 PTVE是一种安全、有效的止血措施,与药物治疗相比可以显著降低病死率,延长再出血间期。     

Pharmacologic treatment of portal hypertension.

Variceal formation and rupture are dreaded complications of chronic liver disease and portal hypertension. The pharmacologic treatment of portal hypertension should be able to stop as well as to prevent variceal hemorrhage. There are two principal types of vasoactive drugs in the treatment of portal hypertension: vasoconstrictors and vasodilators. Vasoconstrictors reduce the splanchnic blood flow, thereby decreasing the portal blood flow and portal pressure. Vasodilators act by different mechanisms, including by relaxation of myofibroblasts in the fibrous septa and presinusoidal areas of the liver and by direct vasodilation of the collateral circulation. In addition, paradoxically, they could decrease portal flow and pressure by inducing a baroreflex-mediated mesenteric arterial vasoconstriction. A miscellaneous group of drugs is also available. These drugs reduce the blood flow and pressure in the gastroesophageal variceal system by mechanisms other than vasoconstriction or vasodilation. The success of these pharmacologic agents is limited once the varices have ruptured. The use of beta-blockers in the prophylaxis of the first variceal bleeding has been proven of benefit in this respect. Future research should be aimed at elucidating the role that humoral and endothelial factors play in development of the hyperdynamic circulatory state that characterizes patients with portal hypertension. Once these etiologic factors have been identified and new knowledge is acquired about their role in the complications of chronic liver disease, the challenge will rest on developing novel pharmacologic therapies specifically targeting these factors.     

Pharmacologic therapy for gastrointestinal bleeding due to portal hypertension and esophageal varices

Cirrhosis results in portal hypertension in many patients. The major complications of portal hypertension include development of ascites and esophageal or gastric varices. Varices lead to hemorrhage and death in a significant proportion of patients. This review focuses on the pharmacologic approach to management of portal hypertension in patients at risk of variceal hemorrhage, or those who have already had variceal bleeding. Pharmacologic therapy is used for 1) primary prevention of bleeding, 2) management of acute bleeding, and 3) prevention of recurrent bleeding (secondary prophylaxis). For acute esophageal variceal hemorrhage, a variety of pharmacologic agents are used, including somatostatin, octreotide, vapreotide, lanreotide, terlipressin, and vasopressin (with nitrates). For primary and secondary prevention of esophageal variceal hemorrhage, a-blockers remain the mainstay therapy.     

Drug therapy of esophageal varices hemorrhage in portal hypertension

The author discusses the etiopathogenesis of portal hypertension and possibilities how to influence it during treatment of acute haemorrhage from varicosities and how to implement primary and secondary prevention. In treatment of acute haemorrhage the author recommends terlipresin, 1 mg every 4 hours. In primary and in particular in secondary prevention he emphasizes the necessity of early administration of beta-blockers.     

内镜下预防食管胃静脉曲张再出血对门静脉系统血流动力学影响的研究

目的评价内镜下预防食管胃静脉曲张患者再出血（二级预防）对门静脉系统血流动力学的影响,以指导临床治疗方案的确定。方法运用超声检查对有出血史的食管胃静脉曲张患者的门静脉系统压力和血流压力包括血管内径、横截面积和平均血流速度进行评价,在二级预防静脉曲张根除后,再次用超声检查评价门静脉系统血流动力学。结果 42例患者在二级预防治疗后1-27个月的随访时间内,达到静脉曲张完全根除,治疗前后超声检查对门静脉系统血流动力学的评估显示,肝动脉内径和肝动脉横截面积显著增宽,其他评估指标治疗前后差异均无统计学意义。结论二级预防治疗静脉曲张再出血,可能使门脉压力有所升高,这需要更大的样本量和长期的跟踪随访来进一步证实。     

Endoscopic measurement of variceal pressure in cirrhosis: correlation with portal pressure and variceal hemorrhage

This study evaluated the clinical application of a pressure-sensitive gauge that allows the noninvasive measurement of the pressure of esophageal varices at endoscopy. The study was performed in 70 patients with cirrhosis and portal hypertension. Among them, 47 had bled from the varices and 23 had varices but had not bled. In addition to measurements of variceal pressure, the size of the varices was estimated semiquantitatively at endoscopy. This allowed an estimate of the tension on the wall of the varices as the product of the transmural pressure and the estimated radius of the varices. Most patients had a standard hemodynamic evaluation of portal hypertension, with measurements of wedged and free hepatic venous pressures, and of azygos blood flow. These were performed within 24 h of the variceal pressure measurements. Variceal pressure was significantly higher in bleeders than in nonbleeders (15.7 +/- 2.8 vs. 12.1 +/- 2.6 mmHg, p less than 0.001) in spite of a similar portal pressure in both groups (20.1 +/- 5.1 vs. 20.4 +/- 7.6 mmHg, NS). More than 60% of the bleeders, but only 22% of the nonbleeders had a variceal pressure greater than or equal to 15 mmHg (p less than 0.005). Among nonbleeders, variceal pressure was higher in patients with large varices (13.9 +/- 2 mmHg, n = 9) than in those with small varices (10.9 +/- 2.4 mmHg, n = 14) (p less than 0.01). Estimates of variceal wall tension further exaggerated the differences between bleeders and nonbleeders (66.1 +/- 22.6 vs. 32.0 +/- 19.8 mmHg.mm, p less than 0.001). More than 50% of bleeders, but just 9% of nonbleeders had an estimated variceal tension greater than 50 mmHg.mm (p less than 0.001). Our findings support the role of an increased variceal pressure in the pathogenesis of variceal hemorrhage, and suggest that this noninvasive technique can be valuable in assessing the risk of variceal hemorrhage in patients with portal hypertension.     

球囊导管栓塞治疗门脉高压症食管胃静脉曲张破裂出血的近期疗效

目的探讨球囊导管栓塞食管胃曲张静脉联合部分脾动脉栓塞(PSE)对门静脉血流动力学的影响,评价其治疗食管胃静脉曲张破裂出血的疗效。方法64例门静脉高压伴食管和(或)胃曲张静脉破裂出血患者,行经皮经肝曲张静脉栓塞术(PTVE),注入无水乙醇和明胶海绵,32例在注入栓寒剂前充盈球囊导管(球囊导管组),另32例不充盈者为对照组,两组均联合PSE。球囊导管组中活动性出血行急症手术者17例,对照组中活动性出血行急症手术者16例。术中直接测门静脉压力。术前、术后彩色多普勒超声测门静脉、脾静脉血流量。数值变量行方差分析和t检验。再出血率和生存率行Kaplan-Meier分析。结果球囊导管栓塞成功率为86.8%,曲张静脉完全栓塞率为100%;对照组PTVE成功率为97.0%,曲张静脉完全栓塞率为87.5%。活动性出血止血率两组均为100%。球囊导管栓塞组曲张静脉栓塞前、后门静脉压力分别为(37.2±1.2)和(41.4±1.1)cm H2O,联合PSE后为(36.7±1.1)cm H2O,对照组分别为(37.2±1.1)、(41.3±1.1)和(36.8±1.1)cm H2O。球囊导管组栓塞前、后门静脉血流量分别为(14.8±1.2)和(14.7±1.1)ml/s(P>0.05),脾静脉血流量分别为(11.8±0.7)和(9.6±0.9)ml/s(P< 0.05);对照组分别为(14.7±1.2)和(14.7±1.2)ml/s(P>0.05),(11.8±0.8)和(9.6±0.9)ml/s(P< 0.05)。球囊导管组6周、12个月再出血率分别为0、6.2%,平均随访774.9 d,曲张静脉再出血率为31.2%.中位再出血时间为832 d;对照组6周、12个月再出血率分别为0、12.5%,平均随访629.3 d,曲张静脉再出血率43.8%,中位再出血时间668 d。球囊导管组出血病死率为15.6%,对照组为25.0%。结论应用球囊导管栓塞食管胃曲张静脉是治疗门静脉高压食管胃曲张静脉出血的有效方法之一。     

门脉高压首次出血的预防进展

静脉曲张出血是肝硬化门脉高压的严重并发症,尽管近年首次静脉曲张出血的死亡率有所下降,但仍是主要死亡原因。目前有人提出用非选择性β受体阻滞剂预防曲张静脉的形成和发展,即一级前预防,并受到重视。非选择性β受体阻滞剂和内镜套扎术(EVL)用于一级预防已较明确。此外,血管紧张素受体抑制剂等药物的运用尚需进一步研究。     

门静脉高压并食管胃底静脉曲张出血的治疗策略

食管胃底静脉曲张破裂出血是门静脉高压的严重并发症,如何控制食管胃底静脉曲张破裂出血并预防再出血,是救治肝硬化患者生命的关键。简述了门静脉高压食管胃底静脉曲张出血的治疗和预防的4个阶段,指出应根据患者不同的临床时期、不同的肝静脉压力梯度、不同的肝功能分级,选择不同的治疗策略。     

经颈静脉肝内门体静脉分流术治疗肝硬化静脉曲张出血预后因素分析

目的 分析经颈静脉肝内门体静脉分流(TIPS)术治疗肝硬化静脉曲张出血患者的预后因素.方法 收集2003年1月至2008年12月162例行TIPS术的肝硬化静脉曲张出血患者基本资料、术前7 d内相关生化指标,定期随访观察术后情况和生存期资料.Cox回归模型评估影响预后生存的指标.结果 TIPS术成功率99%(161/162).中位随访时间21个月.Child-Pugh评分和血小板计数与生存密切相关(P值分别=0.003和0.024).Child-Pughr评分<9分者的累积生存率[75%(102/136)]高于评分≥9分者[50%(13/26),χ2=9.12,P=0.003].血小板计数>47×109/L者的累积生存率[74%(82/112)]高于≤47×109/L者[66%(33/50),χ2=4.528,P=0.033].肝功能Child-Pugh A、B、C级术后1年累积生存率分别为92%、85%、55%.结论 Child-Pugh评分和血小板计数是预测TIPS术治疗肝硬化静脉曲张出血者生存情况的独立因素,当ChildPugh评分≥9分和(或)血小板计数≤47×109/L时术后危险性增加.

Abstract：

Objective To analyze the prognostic factors in treating variceal hemorrhage patients of liver cirrhosis and portal hypertension with transjugular intrahepatic portosystemic shunt (TIPS).Methods From January 2003 to December 2008, the data of 162 variceal hemorrhage patients with liver cirrhosis and portal hypertension treated with TIPS was collected, which included basic information, biochemical examination results within 7 days before the operation, regular follow-up observation after the surgery and survival data. The survival prognostic indexes were assessed with Cox regression model. Results The successful rate of TIPS was 99% (161/162). The median follow up duration was 21 months. Child-Pugh score and blood platelet count (PLT) were closely correlated with survival (P = 0. 003 and 0. 024). The total cumulative survival rate in patients with Child-Pugh score below nine (75%, 102/136) was higher than over nine (50%, 13/26) (χ2 = 9. 12,P=0. 003).The total cumulative survival rate of patients with PLT count over 47 ×109/L (74%, 82/112) was higher than below 47 × 109/L(66 %, 33/50, χ2 =4. 528, P = 0. 033). The one year after operation cumulative survival rate of liver function Child-Pugh class A, B, and C was 92%, 85%, 55% respectively. Conclusion Child-Pugh score and platelet count are independent predictable factors for the survival of variceal hemorrhage patients with liver cirrhosis and portal hypertension treated by TIPS. The risk increase after operation when Child-Pugh score over 9 and/or PLT count less 47×109 /L.     

Colorectal variceal bleeding in patients with extrahepatic portal vein thrombosis and idiopathic portal hypertension.

We report three patients with colonic variceal bleeding secondary to portal hypertension, 0.5% of all cases with hemorrhagic portal hypertension studied by us in the last 16 years. One patient had idiopathic portal hypertension, and the others had extrahepatic portal vein thrombosis. Colonic varices were documented in all three cases by angiogram; large arteriovenous fistulas in the territory of the superior mesenteric artery and between the inferior mesenteric artery and hemorrhoidal veins were demonstrated in one patient. Two patients underwent colonoscopy; colonic varices were seen in only one. Two patients also had bled from esophagogastric varices. One patient underwent descending colon and sigmoid resection after failure to control bleeding with ligation of arterial supply; one patient underwent the Sugiura procedure, plus transanal ligation of hemorrhoids and rectal varices. At 3 months, 2 years, and 4 years of follow-up, the patients were in good general condition without any evidence of rebleeding.     

Drug therapy of portal hypertension

The author presents a list of preparations used to influence portal hypertension resulting from cirrhosis of the liver, in particular in treatment or prevention of haemorrhage from oesophageal varices or gastropathy. The author describes the mechanism of action of drugs administered in acute haemorrhage (vasopressin, terlipressin, somatostatin, octreotide)) and preparations used in primary or secondary prevention of this haemorrhage (beta-blockers, nitrates, newly tested preparations or combinations). In the conclusion are recommendations for practical procedures according to principles of evidence-based medicine.