英国2006肝硬化腹水处理指南.doc

肝硬化腹水处理指南（2006年英国）K P Moore, G P Aithal1.0 INTRODUCTIONAscites is a major complication of cirrhosis,1 occurring in 50% of patients over 10 years of follow up.2 The development of ascites is an important landmark in the natural history of cirrhosis as it is associated with a 50% mortality over two years,25 and signifies the need to consider liver transplantation as a therapeutic option.3 The majority (75%) of patients who present with ascites have underlying cirrhosis, with the remainder being due to malignancy (10%), heart failure (3%), tuberculosis (2%), pancreatitis (1%), and other rare causes.6 The true prevalence and incidence of cirrhosis of the liver and its complications in the UK are unknown. Mortality from cirrhosis has increased from 6 per 100 000 population in 1993 to 12.7 per 100 000 population in 2000.7 Approximately 4% of the general population have abnormal liver function or liver disease8 and approximately 1020% of those with one of the three most common chronic liver diseases (non-alcoholic fatty liver disease, alcoholic liver disease, and chronic hepatitis C) develop cirrhosis over a period of 1020 years. With a rising frequency of alcoholic and non-alcoholic fatty liver disease, a huge increase in the burden of liver disease is expected over the next few years8 with an inevitable increase in the complications of cirrhosis. There have been several changes in the clinical management of cirrhotic ascites over recent years, and the purpose of these guidelines is to promote a consistent clinical practice throughout the UK.1.0绪论腹水是肝硬化的一个主要并发症，1随访超过10年的病人中50发生。2腹水的出现在肝硬化自然史中是一个重要的里程碑，因为其标示着2年间有50的死亡率，2-5而且意味着需要考虑进行肝移植做为治疗方案。3以腹水为表现的病人大部分（75）有潜在的肝硬化，其余的可能是恶性肿瘤（10%）、心衰（3%）、结核（2%）、胰腺炎（1）和其它少见原因。6英国肝硬化真正的流行情况和发生率及其并发症尚不清楚。肝硬化的死亡率已经从1993年的6/10万上升到了2000年的12.7/10万。7普通人群中约4%有肝功能异常或肝病8，患三种最常见的慢性肝病（非酒精性脂肪肝，酒精性脂肪肝和慢性丙型肝炎）之一的病人约10-20在10-20年间会发展成肝硬化。随着酒精性和非酒精性脂肪肝发生率的上升，在今后的数年间肝病的负担会大幅增加8并且不可避免要伴随着肝硬化并发症增加。在最近的几年间肝硬化腹水的临床处理上已有几个变化，本指南的目的是在全英国倡仪一个一致性的临床实践。These guidelines are based on a comprehensive literature search, including the results of randomised control trials, systematic reviews, prospective retrospective studies and, in some instances, evidence obtained from expert committee reports. Where possible a judgement is made on the quality of the information used to generate the guidelines, and the specific recommendations have been graded according to the Oxford Centre for Evidence-based Medicine Levels of Evidence (May 2001) (see appendices 1 and 2).9 These guidelines conform to the international guidelines recently published by the International Ascites Club10 and are intended for use by physicians. We hope to revise these guidelines in three years time.这些指南建立在深入的文献调查基础之上，包括RCT结果，系统综述，前瞻性回顾性研究，在有些情况下，证据是源于专家委员会的报告。如果可能的话，要对产生指南的材料的质量进行判断，并根据剑桥EBM中心的证据水平（2001年5月）（见附录1和2）对详细的建议进行分级。9这些指南符合最近由国际腹水俱乐部10出版的国际指南，也希望为内科医师所用。我们希望在3年的时间内对这些指南进行更新。2.0 DEFINITIONSThe terms used in this article have been defined by the International Ascites Club.11 Uncomplicated ascites Ascites that is not infected and which is not associated with the development of the hepatorenal syndrome. Ascites can be graded as follows: Grade 1 (mild). Ascites is only detectable by ultrasound examination. Grade 2 (moderate). Ascites causing moderate symmetrical distension of the abdomen. Grade 3 (large). Ascites causing marked abdominal distension.Refractory ascitesAscites that cannot be mobilised or early recurrence of which (that is, after therapeutic paracentesis) cannot be satisfactorily prevented by medical therapy. This includes two different subgroups. Diuretic resistant ascitesascites that is refractory to dietary sodium restriction and intensive diuretic treatment (spironolactone 400 mg/day and frusemide 160 mg/day for at least one week, and a salt restricted diet of less than 90 mmol/day (5.2 g of salt)/day). Diuretic intractable ascitesascites that is refractory to therapy due to the development of diuretic induced complications that preclude the use of an effective diuretic dosage.2.0定义本文中所用的词汇已为国际腹水俱乐部所定义。11简单的（无并发症的）腹水指没有被感染的腹水，其与肝肾综合征的出现无关。腹水分级如下：1级（少量）：腹水为超声检查所检测到。2级（中量）：腹水可引起中度对称性的腹部膨胀。3级（大量）：腹水可引起明显的腹胀。难治性腹水药物治疗不能消除腹水或无法满意阻止早期复发（指治疗性腹水穿刺后）。这包括两个不同的亚群。利尿剂抵抗性腹水限盐饮食和增加利尿治疗（安体舒通400mg/d及速尿160mg/d至少一周，饮食中每日盐少于90mmol/d即5.2g盐）腹水仍难以控制。利尿剂难治性腹水由于利尿导致并发症使得有效的利尿剂的量无法应用。3.0 PATHOGENESIS OF ASCITES FORMATIONA detailed description of the pathogenesis of ascites formation is beyond the scope of this article but more detailed reviews are available.1214 There are two key factors involved in the pathogenesis of ascites formationnamely, sodium and water retention, and portal (sinusoidal) hypertension.3.0腹水形成的病机对腹水形成的病机进行详细阐述不在本文的范围，不过有许多详细的综述可以参阅。12-14有两个关键因素涉及到腹水形成的病机，即钠水的潴留和门脉（肝窦）高压。3.1 Role of portal hypertensionPortal hypertension increases the hydrostatic pressure within the hepatic sinusoids and favours transudation of fluid into the peritoneal cavity. However, patients with presinusoidal portal hypertension without cirrhosis rarely develop ascites. Thus patients do not develop ascites with isolated chronic extrahepatic portal venous occlusion or non-cirrhotic causes of portal hypertension such as congenital hepatic fibrosis, except following an insult to liver function such as gastrointestinal haemorrhage. Conversely, acute hepatic vein thrombosis, causing postsinusoidal portal hypertension, is usually associated with ascites. Portal hypertension occurs as a consequence of structural changes within the liver in cirrhosis and increased splanchnic blood flow. Progressive collagen deposition and formation of nodules alter the normal vascular architecture of the liver and increase resistance to portal flow. Sinusoids may become less distensible with the formation of collagen within the space of Disse. While this may give the impression of a static portal system, recent studies have suggested that activated hepatic stellate cells may dynamically regulate sinusoidal tone and thus portal pressure.3.1门脉高压的作用门脉高压增加了肝窦的静水压并促使液体渗透入腹腔。不过，没有肝硬化的窦前性门脉高压病人很少出现腹水。因此，单纯的慢性肝外门脉阻塞或非肝硬化病因的门脉高压如先天性肝纤维化病人是不会出现腹水的，除非是伴随有如胃肠道大出血等引起的肝功能的损害。相反，急性肝静脉血栓形成引起窦后性门脉高压常与腹水有关。门脉高压是硬化肝内结构性变化及内脏血流增加的结果。进行性的胶原沉积以及结节的形成改变了肝内正常的血管系统，使得门脉血流的阻力增加。肝窦的扩张性可能会随着Disse间隙内胶原的形成而更行降低。这给人形成的当然是静态的印象，其实最近的研究已提示肝内星形细胞的激活可能会从动力学上调节肝窦状况进而调节门脉压力。Sinusoidal endothelial cells form an extremely porous membrane which is almost completely permeable to macromolecules, including plasma proteins. In contrast, splanchnic capillaries have a pore size 50100 times less than that of hepatic sinusoids. As a consequence, the trans-sinusoidal oncotic pressure gradient in the liver is virtually zero while it is 0.80.9 (80%90% of maximum) in the splanchnic circulation.12 Oncotic pressure gradients at such extreme ends of the spectrum minimise any effect the changes in plasma albumin concentration may have on transmicrovascular fluid exchange. Therefore, the old concept that ascites is formed secondary to decreased oncotic pressure is false, and plasma albumin concentrations have little influence on the rate of ascites formation. Portal hypertension is critical to the development of ascites, and ascites rarely develops in patients with a wedged hepatic venous portal gradient of12 mm Hg.15 Conversely, insertion of a side to side portacaval shunt to decrease portal pressure often causes resolution of ascites. 肝窦内皮细胞形成的多孔性膜性结构对大分子物质如血浆蛋白几乎完全通透。相反，内脏毛细血管孔径较肝窦的小50-100倍。结果，肝内跨窦的胶体渗透oncotic压力梯度实际上为零而在内脏循环中则为0.8-0.9（最大值的80-90）。12 这样一个范围的极端下oncotic压力梯度会使所有可能的血浆白蛋白浓度的变化对跨越微细血管的液体交换效应减低到最小。所以，腹水的形成是继发于胶体渗透oncotic压力降低这一古老的概念是错误的，血浆白蛋白浓度对于腹水形成速率几乎没有影响。门脉高压对于腹水的出现至关重要，腹水很少出现于肝静脉门脉梯度小于12mmHg的病人。15相反，用以降低门脉压力的侧侧式的门体分流常常会使腹水消退。3.2 Pathophysiology of sodium and water retentionThe classical explanations of sodium and water retention occurring due to underfill or overfill are oversimplified. Patients may exhibit features of either underfill or overfill depending on posture or severity of liver disease. One of the key events thought to be critical in the pathogenesis of renal dysfunction and sodium retention in cirrhosis is the development of systemic vasodilatation, which causes a decrease in effective arterial blood volume and a hyperdynamic circulation.16 The mechanism responsible for these changes in vascular function is unknown but may involve increased vascular synthesis of nitric oxide, prostacyclin, as well as changes in plasma concentrations of glucagon,substance P, or calcitonin gene related peptide.143.2钠水潴留的病理生理学经典的钠水潴留的发生是由于“充盈不佳”或“过度充盈”的解释显然是过于简单了。患者可能表现为要么是“充盈不佳”要么是“过度充盈”的特征取决于姿势或肝病严重程度。在肝硬化中被认为在肾功能不全和钠水潴留发生机制的至关重要的其中一个关键事件是全身血管舒张的出现，这将会导致有效动脉血流量的降低和低动力循环。16血管功能的这些变化的机制还不清楚，不过可能涉及到血管一氧化氮、前列环素合成的降低以及血浆中胰高糖素、P物质浓度或者降钙基因相关钛的变化。14However, the haemodynamic changes vary with posture, and studies by Bernardi et al have shown marked changes in secretion of atrial natriuretic peptide with posture, as well as changes in systemic haemodynamics.17 18 In addition, data showing a decreased effective arterial volume in cirrhosis have been disputed.19 It is agreed however that under supine conditions and in experimental animals, there is an increase in cardiac output and vasodilatation.不过，血流动力学变化会随不同姿势而改变，Bernardi等的研究已经显示心钠素（利钠肽）的分泌会随着不同姿势出现明显的变化。17-18另外，对于显示肝硬化时有效动脉血流量减少的资料现已有所争论。19不过，一致认为在仰卧状态下及实验动物中心输出量和血管舒张有所增加。The development of renal vasoconstriction in cirrhosis is partly a homeostatic response involving increased renal sympathetic activity and activation of the renin-angiotensin system to maintain blood pressure during systemic vasodilatation. 20 Decreased renal blood flow decreases glomerular filtration rate and thus the delivery and fractional excretion of sodium. Cirrhosis is associated with enhanced reabsorption of sodium both at the proximal tubule and at the distal tubule.20 Increased reabsorption of sodium in the distal tubule is due to increased circulating concentrations of aldosterone. However, some patients with ascites have normal plasma concentrations of aldosterone,21 leading to the suggestion that sodium reabsorption in the distal tubule may be related to enhanced renal sensitivity to aldosterone or to other undefined mechanisms.22肝硬化时肾血管收缩的出现，部分是由于全身血管舒张期间涉及到肾交感活性的增加和肾血管紧张素系统的激活以维持血压的稳态反应。20肾血流的减少降低了肾小球滤过率并因而降低钠的传输和部分排泄。肝硬化涉及近、远端小管钠的重吸收增加。20钠在远端小管重吸收的增加是因循环中醛固酮浓度增加，21这提示钠在远端小管的重吸收可能与肾脏对醛固酮或其它不明机制敏感性的增加有关。22In compensated cirrhosis, sodium retention can occur in the absence of vasodilatation and effective hypovolaemia. Sinusoidal portal hypertension can reduce renal blood flow even in the absence of haemodynamic changes in the systemic circulation, suggesting the existence of a hepatorenal reflex.23 24 Similarly, in addition to systemic vasodilation, the severity of liver disease and portal pressure also contribute to the abnormalities of sodium handling in cirrhosis.25 在代偿期肝硬化中，钠潴留可出现于没有血管舒张和有效血容量降低时。甚至在没有全身循环动力学变化时，肝窦门脉高压可减少肾血流量，提示有肝肾反射的存在。23-24同样，除全身血管舒张外，肝病严重程度和门脉压力也会使肝硬化时钠的处置出现问题。254.0 DIAGNOSIS4.1 Initial investigationsThe underlying cause of ascites is frequently obvious from the history and physical examination. However, it is important to exclude other causes of ascites. It should not be assumed that the alcoholic patient has alcoholic liver disease. Therefore, tests must be directed at diagnosing the cause of ascites. The essential investigations on admission include a diagnostic paracentesis with measurement of ascitic fluid albumin or protein, ascitic fluid neutrophil count and culture, and ascitic fluid amylase. Ascitic fluid cytology should be requested when there is a clinical suspicion of underlying malignancy. Other investigations should include abdominal ultrasound scan to evaluate the appearance of the liver, pancreas, and lymph nodes as well as the presence of splenomegaly, which may signify portal hypertension. Blood tests should be taken for measurement of urea and electrolytes, liver function tests, prothrombin time, and full blood count.4.0诊断4.1初始检查（调查，研究）腹水潜在的原因通常可从病史和体检中得到明确。不过排除腹水的其它原因也很重要。不应该去假定嗜酒的病人就有酒精性肝病。所以在腹水原因诊断中必须进行实验室检查。对住院病人必需的检查包括诊断性腹水穿刺以检测腹水白蛋白或蛋白、腹水中性粒细胞计数和培养以及腹水淀粉酶。在临床怀疑有潜在恶性肿瘤时，腹水细胞学检查也应该进行。其它检查还应该包括腹部超声扫描以评估肝表面、胰腺、淋巴结以及脾肿大的存在，这可能标示着有门脉高压。血液检测也应进行以检查尿素氮和电解质、肝功、凝血酶原时间和全血细胞计数。4.2 Abdominal paracentesisThe commonest site for an ascitic tap is approximately 15 cm lateral to the umbilicus, with care being taken to avoid an enlarged liver or spleen, and is usually done in the left or the right lower abdominal quadrant.12 The inferior and superior epigastric arteries run just lateral to the umbilicus towards the mid-inguinal point and should be avoided. For diagnostic purposes, 1020 ml of ascitic fluid should be withdrawn (ideally using a syringe with a blue or green needle) for inoculation of ascites into two blood culture bottles and an EDTA tube, and the tests outlined below. Complications of ascitic taps occur in up to 1% of patients (abdominal haematomas) but are rarely serious or life threatening.26 27 More serious complications such as haemoperitoneum or bowel perforation are rare (,1/1000 procedures).28 Paracentesis is not contraindicated in patients with an abnormal coagulation profile. The majority of patients with ascites due to cirrhosis have prolongation of the prothrombin time and some degree of thrombocytopenia. There are no data to support the use of fresh frozen plasma before paracentesis although if thrombocytopenia is severe (,40 000) most clinicians would give pooled platelets to reduce the risk of bleeding. 4.2腹穿最常选用的腹穿点是脐侧一边约15cm，要注意避开增大的肝脏或脾脏，通常在左或右下腹。12上和下腹主动脉正好于脐到腹股沟中间的一边通过，要注意避开。为诊断目的，要抽10-20ml的腹水（最好用带有兰或绿色针头的注射器）将腹水接种入两个血培养瓶和一个EDTA管，实验会在下边进行描述。腹穿并发症出现于达1的病人（腹部血肿），不过严重的或有生命危险的很少有。26-27更为严重的并发症诸如腹腔内出血或肠穿孔罕见（1/1000）。28凝血机制不正常的患者进行腹穿并无不当。大多数肝硬化腹水的患者凝血酶原时间延长并有一定程度的血小板减少。虽然如果血小板减少严重（40，000）时大多数临床医生会予以浓缩血小板以降低出血的风险，但没有资料支持在腹穿前需要用新鲜冷冻血浆。Recommendationl It is recommended that patients give informed consent for a therapeutic or diagnostic paracentesis.（Level of evidence: 5; recommendation: D.）推荐：l 建议征得病人同意进行诊断或治疗性腹穿（证据水平：5；推荐：D）4.3 Ascitic fluid investigations4.3.1 Ascitic fluid neutrophil count and cultureAll patients should be screened for the development of spontaneous bacterial peritonitis (SBP), which is present in approximately 15% of patients with cirrhosis and ascites admitted to hospital.2931 An ascitic neutrophil count of .250 cells/mm3 (0.25109/l) is diagnostic of SBP in the absence of a known perforated viscus or inflammation of intrabdominal organs. The concentration of red blood cells in cirrhotic ascites is usually ,1000 cells/mm3 and bloody ascitic fluid (.50,000 cells/mm3) occurs in about 2% of cirrhotics.32 In approximately 30% of cirrhotics with bloody ascites, there is an underlying hepatocellular carcinoma.33 However, in 50% of patients with bloody ascites, no cause can be found.33 Grams stain of ascitic fluid is not indicated, as it is rarely helpful.34 The sensitivity of smear for mycobacteria is very poor while fluid culture for mycobacteria has a sensitivity of 50%.35 Several studies have shown that inoculation of ascitic fluid into blood culture bottles will identify an organism in approximately 7290% of cases whereas sending ascitic fluid in a sterile container to the laboratory will only identify an organism in about 40% of cases of SBP.34 36394.3腹水检查4.3.1腹水中性粒细胞计数及培养全部患者需要筛查有无出现自发性细菌性腹膜炎（SBP），约15有肝硬化和腹水的住院患者会出现SBP。29-31在没有已知的内脏穿孔或腹内器官炎症情况下，腹水中性粒细胞计数250/mm3（0.25109/L）对SBP有诊断意义。肝硬化腹水中红细胞通常是1000细胞/mm3，血性腹水（50000细胞/mm3）见于大约2的肝硬化。32有血性腹水的肝硬化中约30有潜在的肝细胞癌。33不过50血性腹水患者找不到原因。33腹水Gram染色没有必要，因为很少有帮助。34涂片找分枝杆菌的敏感性非常差，腹水培养分枝杆菌的敏感性为50。35有多个研究显示腹水接种入血培养瓶中在近72-90的病例会识别出一种微生物，而将腹水加入消毒器皿中送到实验室只在大约40的SBP病例中识别出一种微生物。34，36-39表1 血清腹水白蛋白梯度（SA-AG）SA-AG11g/L SA-AG11g/L 肝硬化 恶性肿瘤心衰 胰腺炎肾病综合征 结核4.3.2 Ascitic fluid protein and ascitic fluid amylaseConventionally, the type of ascites is divided into exudates and transudates, in which the ascitic protein concentration is .25 g/l or ,25 g/l, respectively. The purpose of this subdivision is to help identify the cause of ascites. Thus malignancy classically causes an exudative ascites and cirrhosis causes a transudate. However, there are many misconceptions in clinical practice. For example, it is often presumed that cardiac ascites is a transudate when this is rarely the case, ascitic protein is .25 g/l in up to 30% of patients with otherwise uncomplicated cirrhosis,32 4043 and patients with cirrhosis and tuberculous ascites may have a low ascitic protein.44 The serum ascites-albumin gradient (SA-AG) is far superior in categorising ascites with 97% accuracy (table 1).42 45 46 It is calculated as:SA-AG = serum albumin concentration - ascitic fluid albumin concentrationAs a high ascitic amylase is diagnostic of pancreatic ascites,4749 ascitic fluid amylase should be determined in patients where there is clinical suspicion of pancreatic disease.4.3.2腹水蛋白和腹水淀粉酶按照惯例，腹水分为漏出液和渗出液两种，其腹水蛋白浓度分别是25g/L和25g/L。这样细分的目的是帮助鉴别腹水原因，因此，才有“经典的恶性肿瘤引起渗出性腹水而肝硬化则为漏出性腹水”之说。不过在临床实践中有很多的误解。如通常假定心源性腹水为漏出液而这其实非常少见，在达30的没有并发症的肝硬化病人中腹水蛋白25g/L，32，40-43有肝硬化和结核腹水的病人也可能腹水蛋白很低。44血清腹水-白蛋白梯度（SA-AG）在腹水分类时有更高的优越性，准确率达97%（表1）。42，45-46计算方式如下：SA-AG =血清白蛋白浓度腹水白蛋白浓度因为腹水淀粉酶增高对胰腺性腹水有诊断意义，47-49在临床怀疑有胰腺疾病时应检测患者的腹水淀粉酶。4.3.3 Ascitic fluid cytologyOnly 7% of ascitic fluid cytologies are positive50 yet cytological examination is 6090% accurate in the diagnosis of malignant ascites, especially when several hundred millilitres of fluid is tested and concentration techniques are used.12 Clinicians should liaise with their local cytology department to discuss fluid requirements before paracentesis. But ascites fluid cytology is not the investigation of choice for the diagnosis of primary hepatocellular carcinoma.4.3.3腹水细胞学只有7的腹水细胞学检查阳性50，不过在恶性腹水的诊断中细胞学检查准确率达60-90，