ACITES肝硬化腹水

AASLD PRACTICE GUIDELINE Management of Adult Patients With Ascites Due to Cirrhosis Bruce A. Runyon Preamble These recommendations provide a data-supported ap- proach. They are based on the following: (1) formal re- view and analysis of the recently published world literature on the topic (Medline search); (2) the American College of Physicians’ Manual for Assessing Health Prac- tices and Designing Practice Guidelines1; (3) policy guide- lines, including the American Association for the Study of Liver Diseases’ Policy Statement on Development and Use of Practice Guidelines and the American Gastroen- terological Association’s Policy Statement on the Use of Medical Practice Guidelines,2,3; and (4) the author’s 22 years of experience in the clinical and laboratory investi- gation of, and care of patients with, this problem, includ- ing 7 years’ experience in a liver unit in which approximately 60% of patients have ascites. Intended for use by physicians, these recommenda- tions suggest preferred approaches to the diagnostic, ther- apeutic, and preventative aspects of care. They are intended to be flexible, in contrast to standards of care, which are inflexible policies designed to be followed in every case. Specific recommendations are based on rele- vant published information. Cost-effectiveness and cost- benefit data should be incorporated in the appropriate setting. In an attempt to characterize the quality of evi- dence supporting recommendations, the Practice Guide- lines Committee of the American Association for the Study of Liver Diseases requires a grade to be assigned and reported with each recommendation (Table 1). These guidelines were developed for the care of adult patients with clinically detectable ascites. Although the general approach may be applicable to children, the pedi- atric data base is much smaller and there may be unantic- ipated differences between adults and children. Patients with ascites that is detected by imaging modalities but is not yet clinically evident are not included because of the lack of published information regarding the natural his- tory of this entity. Background Cirrhosis was the tenth leading cause of death in the United States, according to a 2000 Vital Statistics Report, in which data was collected through 1998.4 Ascites is the most common of the 3 major complications of cirrhosis; the other complications are hepatic encephalopathy and variceal hemorrhage.5 Approximately 50% of patients with “compensated” cirrhosis, i.e., without having devel- oped one of these complications, develop ascites during 10 years of observation.5 Development of fluid retention in the setting of cirrhosis is an important landmark in the natural history of chronic liver disease: approximately 50% of patients with ascites succumb in 2 years.6 Many patients are referred for liver transplantation after devel- opment of ascites. Literature Review A Medline search from 1966 through 2002 was per- formed; search terms included ascites, diet therapy, drug therapy, radiotherapy, surgery, and therapy. The search involved only papers published in English and involving humans. A manual search of the author’s files was also performed. The search yielded 1,867 papers including 411 published since a similar search was performed in 1997 in preparation for writing the previous guideline on ascites.7 Evaluation and Diagnosis History Most patients (approximately 85%) with ascites in the United States have cirrhosis.8 In about 15% of patients with ascites, there is a nonhepatic cause of fluid retention. Successful treatment is dependent on an accurate diagno- sis of the cause of ascites; e.g., peritoneal carcinomatosis does not respond to diuretic therapy. Patients with ascites should be questioned about risk factors for liver disease. Those who lack an apparent cause for cirrhosis should also Abbreviations: SAAG, serum-ascites albumin gradient; PMN, polymorphonu- clear leukocyte; TIPS, transjugular intrahepatic portasystemic stent-shunt; SBP, spontaneous bacterial peritonitis. From the Rancho Los Amigos Medical Center, Downey, CA. Received September 9, 2003; accepted September 17, 2003. This is a revised and updated guideline based on the previously published version (HEPATOLOGY 1998;27:264–272). Address reprint requests to: Bruce A. Runyon, M.D., Chief, Liver Service, Loma Linda University Medical Center, 11234 Anderson Street, Room 1556, Loma Linda, CA 92354. E-mail: brunyon@ahs.llumc.edu; fax: 909-558-0274. Copyright © 2004 by the American Association for the Study of Liver Diseases. Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hep.20066 1 be questioned about lifetime body weight; nonalcoholic steatohepatitis has been concluded to be causative in many of these patients.9 Past history of cancer, heart fail- ure, or tuberculosis is also relevant. Hemophagocytic syn- drome can masquerade as cirrhosis with ascites.10 These patients have fever, jaundice, and hepatosplenomegaly, usually in the setting of lymphoma or leukemia.10 Physical Examination The presence of a full, bulging abdomen should lead to percussion of the flanks. If the amount of flank dullness is greater than usual (i.e., if the percussed air-fluid level is higher than normally found on the lateral aspect of the abdomen with the patient supine), one should test for “shifting.” Approximately 1,500 mL of fluid must be present before flank dullness is detected.11 If no flank dullness is present, the patient has less than a 10% chance of having ascites.11 The fluid wave and puddle sign are not useful.11 Ascites due to alcoholic cardiomyopathy can mimic that due to alcoholic cirrhosis. Jugular venous dis- tension is present in the former but not in the latter. The physical examination for detecting ascites in the obese patient is problematic. An abdominal ultrasound may be required to determine with certainty if fluid is present. The diagnosis of new-onset ascites is suspected on the basis of the history and physical examinationand usually confirmed by successful abdominal paracentesis and/or ultrasound. The diagnosis of the cause of ascites forma- tion is based on the results of the history, physical, and ascitic fluid analysis. In general, few other tests are re- quired. However, the liver is commonly imaged (usually with ultrasound) to screen for hepatocellular carcinoma, portal vein thrombosis, and hepatic vein thrombosis. Abdominal Paracentesis Abdominal paracentesis with appropriate ascitic fluid analysis is probably the most rapid and cost-effective method of diagnosing the cause of ascites.12,13 Fluid due to portal hypertension can be readily differentiated from fluid due to other causes.8 Also, in view of the high prev- alence of ascitic fluid infection at the time of admission to the hospital, an admission surveillance tap may detect unexpected infection.14 Although older published series reported a relatively high morbidity, and even mortality, when trocars were used for paracentesis, more recent studies regarding para- centesis complications in patients with ascites docu- mented no deaths or infections caused by the paracentesis.15 Complications were reported in only about 1% of patients (abdominal wall hematomas), de- spite the fact that 71% of the patients had an abnormal prothrombin time.15 Although more serious complica- tions (hemoperitoneum or bowel entry by the paracente- sis needle) occur,16 they are sufficiently unusual (�1/1,000 paracenteses) that they should not deter per- formance of this procedure. It is the practice of some physicians to give blood products (fresh frozen plasma and/or platelets) routinely before paracentesis in cirrhotic patients with coagulopathy. This policy is not data-sup- ported. The risks and costs of prophylactic transfusions exceed the benefit. In the past, the midline was usually chosen as the site for paracentesis. However, the abdominal wall in the left lower quadrant, 2 finger breadths cephalad and 2 finger breadths medial to the anterior superior iliac spine, has been shown to be thinner and with a larger pool of fluid than the midline.17 If the fluid is difficult to localize by examination because of obesity, ultrasonography can be useful. There are few contraindications to paracentesis. Co- agulopathy should preclude paracentesis only when there is clinically evident fibrinolysis or clinically evident dis- seminated intravascular coagulation.15 These conditions occur in less than 1 per 1,000 procedures. There is no data-supported cutoff of coagulation parameters beyond which paracentesis should be avoided.15 Recommendations 1. Abdominal paracentesis should be performed and ascitic fluid should be obtained from inpatients and out- patients with clinically apparent new-onset ascites. (Grade II-3) 2. Since bleeding is sufficiently uncommon, the pro- phylactic use of fresh frozen plasma or platelets before paracentesis is not recommended. (Grade III) Ascitic Fluid Analysis Future outcomes studies are required to determine the optimal testing strategy. Meanwhile, an algorithm ap- proach seems preferable to ordering a large number of tests on most specimens. If uncomplicated cirrhotic as- cites is suspected, only screening tests (e.g., cell count and differential, albumin and total protein concentration) are Table 1. Quality of Evidence on Which a Recommendation Is Based* Grade Definition I Randomized controlled trials II-1 Controlled trials without randomization II-2 Cohort or case-control analytic studies II-3 Multiple time series, dramatic uncontrolled experiments III Opinions of respected authorities; descriptive epidemiology *Data from Woolf and Sox.3 2 RUNYON HEPATOLOGY, March 2004 performed on the initial specimen. If the results of these tests are unexpectedly abnormal, further testing can be performed on another ascitic fluid sample. Also, many laboratories save an aliquot of fluid for a few days; this fluid can be tested if the specimen has been handled prop- erly. However, since most specimens are consistent with uncomplicated cirrhotic ascites, no further testing will be needed in the majority of patients. If ascitic fluid infection is suspected (fever, abdominal pain, or unexplained encephalopathy), bacterial culture in blood culture bottles should be performed. Use of a urine dipstick to detect neutrophils in ascitic fluid takes only 90 seconds to 2 minutes; if confirmed by other studies, this may become a routine method of providing early suspi- cion of infection.18,19 Automated cell counting has been shown to be accurate; the result is rapidly available and thus may replace the manual cell count.20 Additional test- ing, e.g., total protein, lactate dehydrogenase, and glucose to assist in differentiating spontaneous from secondary bacterial peritonitis, can be performed on the initial spec- imen based on clinical judgment.21 An ascitic fluid carci- noembryonic antigen greater than 5 ng/mL or ascitic fluid alkaline phosphatase greater than 240 units/L has also been shown to be accurate in detecting gut perforation into ascitic fluid.22 The serum-ascites albumin gradient (SAAG) has been proved in prospective studies to categorize ascites better than the total-protein-based exudate/transudate concept and better than modified pleural fluid exudate/transudate criteria.8,23 Calculating the SAAG involves measuring the albumin concentration of serum and ascitic fluid speci- mens obtained on the same day and subtracting the ascitic fluid value from the serum value. If the SAAG is greater than or equal to 1.1 g/dL (11g/L), the patient has portal hypertension, with approximately 97% accuracy.8 Pa- tients who have portal hypertension plus a second cause for ascites formation also have a SAAG greater than or equal to 1.1g/dL. Patients undergoing serial outpatient therapeutic para- centeses probably should be tested only for cell count and differential (the author has detected 8 episodes of sponta- neous bacterial peritonitis in approximately 400 paracen- teses in a paracentesis clinic in 2 years [Zeid Kayali, Reza Khoshini, B.A.R., outpatient management of refractory ascites, unpublished observations, 2003]). Bacterial cul- ture is not necessary in asymptomatic patients undergoing serial large-volume paracenteses.24,25 The most expensive tests are the cytology and smear and culture for mycobacteria; these tests should probably be ordered only when there is a high pretest probability of occurrence of the disease under consideration. The ascitic fluid cytology is positive only in the setting of peritoneal carcinomatosis.26 The sensitivity of cytology in detecting peritoneal carcinomatosis is 96.7% if 3 samples are sent and processed promptly; the first sample is positive in 82.8% and at least 1 of 2 samples is positive in 93.3%.26 In this study, 50 mL of fresh warm ascitic fluid were hand-carried to the laboratory for immediate processing. Patients with peritoneal carcinomatosis usually have a his- tory of a breast, colon, gastric, or pancreatic primary car- cinoma. The sensitivity of smear for mycobacteria is approximately 0%; the sensitivity of fluid culture for my- cobacteria is approximately 50%.27 Only patients at high risk for tuberculous peritonitis (e.g., recent immigration from an endemic area or acquired immunodeficiency syn- drome)28 should have testing for mycobacteria on the first ascitic fluid specimen. Laparoscopy with biopsy and my- cobacterial culture of tubercles are the most rapid and accurate methods of diagnosing tuberculous peritonitis. Multiple prospective trials have shown that bacterial growth occurs in only about 50% of instances when as- citic fluid with a polymorphonuclear leukocyte (PMN) count greater than or equal to 250cells/mm3 (0.25 � 109/L) is cultured by older methods as compared to ap- proximately 80% if the fluid is inoculated into blood culture bottles at the bedside.29,30 Recommendations 3. The initial laboratory investigation of ascitic fluid should include an ascitic fluid cell count and differential, ascitic fluid total protein, and SAAG. (Grade II-2) 4. If ascitic fluid infection is suspected, ascitic fluid should be cultured at the bedside in blood culture bottles. (Grade II-2) 5. Other studies can be ordered based on pretest probability of disease (Table 2). (Grade III) Differential Diagnosis Although cirrhosis is the cause of ascites formation in most patients, approximately 15% have a cause other than liver disease, including cancer, heart failure, tuberculosis, or nephrotic syndrome.8 Approximately 5% of patients with ascites have 2 or more causes of ascites formation, i.e., “mixed” ascites.8 Usually, these patients have cirrhosis plus 1 other cause, e.g., peritoneal carcinomatosis or peri- toneal tuberculosis. Many patients with enigmatic ascites are eventually found to have 2 or even 3 causes for ascites formation (e.g., heart failure, diabetic nephropathy, and cirrhosis due to nonalcoholic steatohepatitis). In this set- ting, the sum of predisposing factors leads to sodium and water retention when each individual factor might not be severe enough to cause fluid overload. HEPATOLOGY, Vol. 39, No. 3, 2004 RUNYON 3 Treatment of Ascites Appropriate treatment of patients with ascites depends on the cause of fluid retention. SAAG can be helpful diagnostically as well as in decision-making regarding treatment. Patients with low SAAG ascites usually do not have portal hypertension and, with the exception of ne- phrotic syndrome, do not respond to salt restriction and diuretics.13 In contrast, patients with a high SAAG have portal hypertension and usually are responsive to these measures.13 The remainder of this guideline is applicable only to patients with cirrhosis as the cause of their ascites. Im- provement in the outcome of patients with nonportal- hypertension-related ascites depends on successful treatment of the underlying disorder. Alcohol-induced liver injury is perhaps the most re- versible cause of liver disease that leads to high albumin gradient ascites.13 One of the most important steps in treating ascites in this setting is to treat the underlying liver disease by convincing the patient to stop drinking alcohol. In a period of months, abstinence can result in dramatic improvement in the reversible component of alcoholic liver disease. One recent study demonstrates that patients who have Child-Pugh C cirrhosis due to alcohol and who stop drinking have an approximately 75% 3-year survival, but all those who continue to drink die in 3 years.31 Ascites may resolve or become more re- sponsive to medical therapy with abstinence and time. Nonalcoholic liver diseases are less reversible; by the time ascites is present, these patients may be better candidates for liver transplantation than protracted medical therapy. The mainstays of treatment of patients with cirrhosis and ascites include (1) education regarding dietary so- dium restriction (2000 mg per day [88 mmol per day]) and (2) oral diuretics.12,13 More stringent dietary sodium restriction can speed mobilization of ascites. Fluid loss and weight change are directly related to sodium balance in patients with portal-hypertension-related ascites. It is sodium restriction, not fluid restriction, which results in weight loss; fluid follows sodium passively.32 Measure- ment of urinary sodium excretion is a helpful parameter to follow when rapidity of weight loss is less than de- sired.12,13 Random urinary sodium concentrations are of value when they are 0 mmol/L or greater than 100 mmol/L but are much less helpful when they are interme- diate because of lack of uniformity of sodium excretion during the day and lack of knowledge of total urine vol- ume, which may vary from 300 mL to greater than 3000 mL. Twenty-four-hour collections of urine for determi- nation of sodium excretion are much more informative than random specimens; however, full-day collections are cumbersome. Providing patients with verbal and written instructions, a container, and a lab order slip to turn in with the completed specimen helps insure compliance. Completeness of collection of the 24-hour specimen can be assessed by measurement of urinary creatinine. Cir- rhotic men should excrete more than 15 mg of creatinine per kilogram of body weight per day, and women should excrete more than 10 mg/kg per day.33 Less creatinine is indicative of an incomplete collection. Total nonurinary sodium excretion is less than 10 mmol per day in afebrile cirrhotic patients without diarrhea.34 One of the goals of treatment is to increase urinary excretion of sodium so that it is greater than 78 mmol per day (88 mmol intake per day� 10 mmol nonurinary excretion per day). Only the 10% to 15% of patients who have spontaneous natriuresis greater than 78 mmol per day can be considered for dietary sodium restriction alone (i.e., without diuretics). However, when given a choice, most patients would prefer to take some diuretics and have a more liberal sodium intake than take no pills and have a more severe sodium restriction. A random “spot” urine sodium concentration that is greater than the potassium concentration correlates with a 24-hour sodium excretion greater than 78 mmol per day with approximately 90% accuracy.35 This urine sodium/ potassium ratio may replace the cumbersome 24-hour collection. Fluid restriction is not necessary in treating most pa- tients with cirrhosis and ascites. The chronic hyponatre- mia usually seen in cirrhotic ascites patients is seldom morbid. Attempts to rapidly correct hyponatremia in this setting with hypertonic saline can lead to more complica- Table 2. Ascitic Fluid Laboratory Data* Routine Optional Unusual Unhelpful Cell count and differential Culture in blood culture bottles AFB smear and culture pH Albumin Glucose Cytology Lactate Total protein Lactate dehydrogenase Triglyceride Cholesterol Amylase Bilirubin