Cirrhosis of the liver is a chronic illness that progresses at a variable rate, dependent on the etiology and the activity of the offending toxin. It is a dynamic process, which is potentially reversible in the earlier stages if the offending agent is either removed or modified. Classically, cirrhosis has been defined histologically as architecturally abnormal nodules separated by bands of fibrous tissue. The diagnosis has usually been based on clinical suspicion, confirmed by radiologic studies and a liver biopsy as the gold standard. However, sampling error on biopsy may lead to incorrect staging of the disease, where the transition from severe fibrosis to cirrhosis is misinterpreted. Therefore, advanced chronic liver disease has been proposed as a more encompassing definition for the transitional stages. However, in this chapter, we will continue to use cirrhosis as the term to characterize this entity.
Patients with cirrhosis may be further classified as compensated or decompensated. Decompensation is defined as the appearance of ascites, variceal bleeding, hepatic encephalopathy or jaundice. A prognostic classification consisting of five stages has been proposed to account for the increasing mortality with progressive decompensation (Figure 160-1). Stage one includes patients with compensated cirrhosis that do not have any complications such as ascites or esophageal varices. In stage two, patients have developed nonbleeding esophageal varices but are still considered compensated. Stage three describes patients who have transitioned to decompensation, characterized by the development of hemorrhage from esophageal varices. Patients may further progress to stage four which is characterized by the development of nonbleeding complications, including the development of ascites, hepatic encephalopathy or the hepatorenal syndrome. Stage five includes patients who have developed a second decompensating event. In a recent study by D’Amico et al that included 494 patients with alcoholic, viral or cryptogenic cirrhosis, the initial decompensating event was ascites (33%), variceal bleeding (10%), and hepatocellular carcinoma (9%), while encephalopathy or jaundice as the first decompensating event was rare. In this study, the 5-year mortality was 1.5% for patients in stage one compared to 88% for patients in stage five. In addition to describing the natural history of the disease process, a potential benefit of this staging system is the ability to target specific therapy based on the prognosis at a given stage. For example, patients who presented with variceal bleeding without ascites had a significantly better survival than those in whom ascites was present at the onset of the bleeding event and would be less likely to be considered as candidates for liver transplantation.
Schematic representation of 5-year transitioning rate across stages and to death for the whole series of patients. Arrows represent transitions and the numbers close to each arrow are the relevant transition rates. A fairly steady increase in death rate was found across stages. (From D’Amico G, et al. Competing risks and prognostic stages of cirrhosis: a 25-year inception cohort study of 494 patients. Aliment Pharmacol Ther. 2014;39(10):1180-1193.)
The major complications of cirrhosis are secondary to the development of portal hypertension. The initiating event is an increase in intrahepatic and portocollateral resistance, followed by an increase in portal venous flow. The increase in intrahepatic resistance has relatively fixed components including sinusoidal encroachment, collagen deposition, vascular tree pruning and nodular formation. Dynamic components of intrahepatic resistance are governed by an overexpression of endogenous vasoconstrictors, especially endothelin, and a diminished expression of vasodilators, primarily nitric oxide. The increase in portal blood flow is related to systemic vasodilation secondary to increased systemic production of vasodilators, primarily nitric oxide but also including increased production of glucagon, tumor necrosis factor, prostaglandins and other cytokines. The resulting hyperdynamic circulation leads to an increase in portal venous blood flow against intrahepatic resistance, resulting in portal hypertension. Portal hypertension is further aggravated by an increase in angiogenesis which exacerbates the increase in portal pressure and promotes the development of a portosystemic collateral circulation including the development of esophageal varices.
Presenting symptoms of cirrhosis are nonspecific and include the development of fatigue and lethargy. Physical findings include jaundice, peripheral muscle wasting, splenomegaly, spider angiomata, abdominal collateral vessels and an altered mental status. However, patients presenting initially with cirrhosis often have none of these findings.
Laboratory findings include an increase in serum bilirubin, a decrease in serum albumin, increases in AST, ALT and alkaline phosphatase and prolongation of the prothrombin time. A decrease in platelet count in the presence of cirrhosis suggests the development of portal hypertension but the variability of this finding makes it unreliable as a screening test.
Although liver biopsy remains the gold standard for the diagnosis of cirrhosis, the test is invasive, often limited by inadequate sample size and prone to sampling error. Recently, there is increased interest in noninvasive means for diagnosing cirrhosis. Most prominent of the noninvasive methods is the use of transient elastography (TE) (fibroscan) as a means of identifying patients with cirrhosis who are at risk of developing clinically significant portal hypertension. The technique is easy to perform at bedside, has excellent reproducibility, and has very good correlation with invasive measurements of portal pressure (eg, the hepatic venous pressure gradient [HVPG]), especially in patients in the compensated stages of cirrhosis. Limitations include occasional false positives and unreliability in obese patients, patients with clinically evident ascites and patients with acute liver failure. The fibroscan has recently received Food and Drug Administration (FDA) approval and has become a standard diagnostic test in liver centers throughout Europe and North America.
Other noninvasive methods for the diagnosis of cirrhosis include serum biomarkers (eg, Fibrotest) which have gained popularity in Europe, more so than in the United States. A number of radiologic approaches are under investigation including MR elastography, ultrasound elastography and measurements of splenic stiffness but these should still be considered experimental techniques.
Portal pressure as measured by the HVPG provides excellent information for diagnosis, prognosis and management of portal hypertension. Hepatic venous pressure gradient measurements are excellent in predicting the development of esophagogastric varices, ascites, esophageal variceal hemorrhage, hepatic decompensation and the development of hepatocellular carcinoma. Hepatic venous pressure gradient measurements are especially useful in assessing response to pharmacologic therapy of portal hypertension. However, because of the invasive nature of these measurements, they are primarily used in clinical research studies and have limited usage in clinical practice.
Patients with cirrhosis can be classified as compensated or decompensated.
Decompensation is defined as the appearance of ascites, variceal bleeding, hepatic encephalopathy or jaundice.
A prognostic classification consisting of five stages has been proposed to account for the increasing mortality with progressive decompensation. The 5-year mortality is 1.5% for patients in stage one compared to 88% for patients in stage five.
Patients with cirrhosis develop esophageal varices at a rate of 8% per year. The risk of hemorrhage from varices is 5% to 15% per year, with patients having large varices at greater risk. Variceal hemorrhage is associated with a 15% to 20% 6-week mortality. If the index bleed is controlled and no further treatment to prevent rebleeding is initiated, the risk of recurrent hemorrhage is 60% to 70% with most episodes occurring within 1 year of the index bleed.
SCREENING FOR ESOPHAGEAL VARICES
Current practice guidelines recommend screening by esophagogastroduodenoscopy (EGD) for the presence of varices in all patients with the diagnosis of cirrhosis. In patients with compensated cirrhosis and no varices on the initial screening EGD, the EGD should be repeated in 2 to 3 years unless there is evidence of clinical progression of the disease. In patients with decompensated cirrhosis and no varices on the initial examination, EGD should be repeated yearly. Once varices have been detected, further EGD is not indicated unless there is evidence of gastrointestinal bleeding. Because of cost and patient preference considerations, there is considerable interest in noninvasive techniques that might identify patients with cirrhosis at low risk for the development of varices. Noninvasive serum markers combining a number of biochemical tests may identify patients at low risk for developing varices but their positive and negative predictive values are insufficient to avoid screening endoscopy. A low platelet count (<100,000/mm2) has been suggested for screening patients at risk for varices but the predictive accuracy is insufficient to defer patients from endoscopic screening. The platelet count/spleen diameter ratio as measured by abdominal ultrasound is somewhat better at identifying patients at risk. The best noninvasive test for identifying patients at low risk for the development of varices is the measurement of liver stiffness by transient elastography. In patients with TE values <10 kPa in the absence of clinical signs of portal hypertension, the risk of developing esophageal varices is extremely low and screening endoscopy may be avoided. Until more data are available, patients with a TE value >10 kPa should be screened by endoscopy for varices. If the TE value is >15 kPa, patients are at high risk for developing varices. Wireless capsule endoscopy has 85% to 95% accuracy in determining the presence of varices, variceal size and endoscopic red color signs. However, this technique is not widely available and it has not replaced endoscopic screening as the standard diagnostic procedure.
RISK STRATIFICATION FOR VARICEAL HEMORRHAGE
With rare exceptions, patients with cirrhosis require an HVPG >10 mm Hg for the development of esophageal varices and an HVPG >12 mm Hg for variceal hemorrhage to occur. Risk factors for variceal hemorrhage as identified by endoscopy include the size of varices (large varices are at greater risk than small varices) and the endoscopic red color signs. The latter include red wale marks that appear as longitudinal red streaks on varices, hematocystic spots which look like small varices on the surface of larger varices and cherry red spots. In addition, the worse the Child-Pugh score, the greater the risk of bleeding. In patients with alcoholic cirrhosis, active alcohol consumption increases the risk of hemorrhage.
TREATMENT OF ESOPHAGEAL VARICES AND VARICEAL HEMORRHAGE
Options for the treatment of esophageal varices include pharmacologic agents that decrease portal pressure, endoscopic techniques that obliterate the varices and TIPS (transjugular intrahepatic portosystemic shunt) or surgical shunts that achieve a major reduction in portal pressure.
The goal of pharmacologic therapy is to reduce portal venous blood flow and/or intrahepatic and portocollateral resistance in order to achieve a decrease in portal pressure. The primary drugs to achieve this goal on a long-term basis are the nonselective β-blockers (propranolol, nadolol, and timolol) and the long acting nitrate, isosorbide-5-mononitrate (ISMN).
β-Blockers act by decreasing cardiac output via blockade of the β1 receptors and by blockade of the β2 receptors, leaving unopposed alpha adrenergic activity which causes vasoconstriction of the splanchnic vessels. These drugs are given orally and should be titrated to the maximally tolerated dose. Unfortunately, only 35% to 40% of patients treated with β-blockers achieve a clinically significant hemodynamic response, defined as a 20% reduction in HVPG or a reduction in HVPG to below 12 mm Hg. Carvedilol, a nonselective β-blocker with intrinsic anti-alpha-1 adrenergic activity has been shown to produce a greater reduction in HVPG than the nonselective β-blockers when given as monotherapy.
Isosorbide-5-mononitrate increases the delivery of nitric oxide to the intrahepatic circulation, thus decreasing intrahepatic resistance. It also decreases cardiac output by decreasing cardiac preload and enhances systemic vasodilation and venous pooling which causes a reflex splanchnic arterial vasoconstriction. When given together with nonselective β-blockers, there is an incremental reduction in HVPG. Isosorbide-5-mononitrate is clinically ineffective when given as monotherapy.
Simvastatin has been shown to produce an incremental decrease in the HVPG when combined with nonselective β-blockers and prospective trials are currently underway to determine its clinical efficacy.
The major side effects of nonselective β-blockers include hypotension, fatigue, lethargy, depression and dyspnea in patients with pulmonary disease. Their use is contraindicated in patients with restrictive airway disease, congestive heart failure, bradycardia and heart block. Their use in insulin dependent diabetics needs to be monitored carefully. As a result, 15% to 20% of patients with cirrhosis have contraindications to the use of β-blockers, and an additional 15% develop severe side effects leading to discontinuation of the drug. The major side effects of ISMN are systemic arterial hypotension and headaches.
The drugs used in the management of acute variceal bleeding include the vasopressin analog, terlipressin and somatostatin and its analogs, octreotide, vapreotide and lanreotide. The goal of these drugs is to reduce portal venous blood flow and portal pressure Terlipressin achieves a greater reduction in portal pressure than the somatostatin analogs. The drugs are safe with minimal side effects (Table 160-1).
TABLE 160-1Drugs Used in the Management of Portal Hypertension ||Download (.pdf) TABLE 160-1 Drugs Used in the Management of Portal Hypertension
|Drug ||Class of Drug ||Starting Dose ||Maximum Dose |
|Propranolol ||Nonselective β-blocker ||40 mg twice daily ||640 mg/d |
|Nadolol ||Nonselective β-blocker ||40 mg daily ||320 mg/d |
|Timolol ||Nonselective β-blocker ||10 mg daily ||40 mg/d |
|Carvedilol ||Nonselective β-blocker with intrinsic anti-α adrenergic activity ||6.25 mg ||12.5 mg/d |
|Isosorbide mononitrate ||Long-acting nitrate ||20 mg daily ||240 mg/d |
|Spironolactone ||Aldosterone antagonist ||25 mg daily ||400 mg/d |
|Furosemide ||Loop diuretic ||40 mg daily ||160 mg/d |
|Octreotide ||Splanchnic vasoconstrictor ||50 μg bolus, followed by 50 μg/h or subcutaneously 100-200 mg three times daily ||50 μg/h |
Oral alpha-1 agonist
Intravenous vasopressin analog
Intravenous alpha 1 and beta 1 agonist
400 mg twice daily
5 mg three times daily
1-2 mg every 4-6 h
Unfortunately, none of these drugs (mostly generic) have received FDA approval specifically for the treatment of esophageal varices and variceal hemorrhage. The nonselective β-blockers and octreotide are used off label. Terlipressin is widely used in Europe but as yet, has not received FDA approval for use in the US.
ENDOSCOPIC VARICEAL LIGATION (EVL)
Endoscopic variceal ligation involves the placement of rubber bands on the variceal columns via an endoscope that causes mucosal and submucosal necrosis leading to the formation of scar tissue and the obliteration of the varix. It is a local treatment and does not significantly alter portal hypertension. The most serious side effects are possible perforation of the esophagus and the formation of mucosal ulcers that can lead to significant hemorrhage. Endoscopic variceal ligation has replaced sclerotherapy as the endoscopic treatment of choice.
TRANSJUGULAR INTRAHEPATIC PORTOSYSTEMIC SHUNT (TIPS)
The TIPS procedure involves placement of a catheter into the right internal jugular vein and advancing it via the hepatic vein through the liver to form a tract connecting to the portal vein. This transhepatic tract is then dilated and a flexible coated metallic stent is placed, resulting in a shunt between the hepatic and portal veins and a significant decrease in portal pressure. The procedure is performed by interventional radiologists and has replaced portosystemic shunt surgery in most institutions.
Short-term complications of the TIPS procedure include fever, infection, renal dysfunction, intrahepatic and intraperitoneal hemorrhage and progressive hepatic failure. The major long-term complication is the development or worsening of hepatic encephalopathy, which has an incidence of approximately 30% to 35%. Risk factors for the development or worsening of hepatic encephalopathy after TIPS include increasing age, the presence of minimal hepatic encephalopathy at the time of TIPS placement, and a history of overt hepatic encephalopathy. The severity of encephalopathy correlates with the diameter of the shunt. With the advent of coated stents, shunt occlusion is much less of a problem. Doppler sonography is a noninvasive method to monitor shunt patency and is usually performed at 6-month intervals for the first 2 years after TIPS placement.
PREVENTION OF FIRST VARICEAL HEMORRHAGE (PRIMARY PROPHYLAXIS)
Based on the results of a large, long-term, multicenter randomized controlled trial (RCT), there was no benefit for the use of nonselective β-blockers in the prevention of the development of esophageal varices or other complications of portal hypertension in patients with compensated cirrhosis and an elevated HVPG.
Because of the high risk of bleeding and the associated mortality, treatment to prevent initial variceal hemorrhage is mandatory. Current practice guidelines (AASLD, ACG, Baveno) recommend the use of either nonselective β-blockers or EVL for the prevention of variceal hemorrhage in patients with large varices or small varices in patients with Child-Pugh class C cirrhosis or in patients with small varices when red color signs are present on endoscopy. In other patients with small varices, β-blockers may be used, but more data are needed to establish their efficacy. A meta-analysis of 11 RCTs totaling 1190 patients showed a reduction in first variceal hemorrhage in patients with large varices from 30% in the control groups to 14% in the treatment groups. Randomized controlled trials showed similar results when comparing EVL to control groups. Neither treatment has been shown to improve survival. In well-designed RCTs with reasonable sample sizes, β-blockers and EVL were equally effective. As they are comparable in efficacy, the choice should be based on local expertise, side effects of the treatment and patient preference. In patients in whom varices have been eradicated with EVL, surveillance endoscopy should be performed because of the risk of recurrent variceal formation. However, EVL only reduces the risk of variceal bleeding while nonselective β-blockers reduce the risk of other complications of portal hypertension (ie, ascites) in addition to variceal bleeding.
TREATMENT OF ACUTE VARICEAL HEMORRHAGE
In patients with acute upper gastrointestinal bleeding, the source of bleeding should be determined by endoscopy. If varices are suspected in patients with cirrhosis, the patient should be started on a vasoactive drug (eg, terlipressin, octreotide). The vasoactive drugs should be continued for up to 5 days. Intubation to protect the airway is recommended in patients with active bleeding or altered mental status. In the absence of contraindications (eg, QT prolongation), infusion of erythromycin 250 mg IV 30 to 120 minutes prior to endoscopy should be considered (Figure 160-2).
Management algorithm for acute variceal hemorrhage. EGD, esophagogastroduodenoscopy; EVL, endoscopic variceal ligation. (From Grace ND, Minor MA. Portal hypertension and variceal hemorrhage. In: Greenberger NJ, Blumberg RS, Burakoff R (eds). Current Diagnosis and Treatment: Gastroenterology, Hepatology and Endoscopy. New York, McGraw Hill Education Medical, 2016.)
A hemoglobin of 8.0 g/dL or a hematocrit of 25% should be the goal of transfusion in order to avoid an increase in portal pressure and exacerbation of the bleeding episode associated with overtransfusion. If the platelet count is greater than 50,000, platelet transfusions are not warranted. If the platelet count is lower, the use of platelet transfusions is controversial and their use has not been shown to affect the bleeding episode. The use of fresh frozen plasma (FFP) or recombinant factor VII transfusions is also controversial without clear evidence of their efficacy.
In patients with acute variceal bleeding, infection has been associated with early rebleeding and a high mortality rate. Based on the results of several RCTs, the short-term use of prophylactic antibiotics is mandatory. Preferred antibiotics include norfloxacin (400 mg twice daily for 7 days) or quinolone antibiotics (eg, levofloxacin, ciprofloxacin). In patients with decompensated cirrhosis, intravenous ceftriaxone (1.0 g/d) has been shown to be superior to norfloxacin. As there is increasing hospital based drug resistance to quinolones, this should be considered in the choice of antibiotics. If there is evidence of hepatic encephalopathy, institution of lactulose or rifaximin is recommended.
Once esophageal varices have been established as the source of bleeding, esophageal variceal ligation should be instituted to control the bleeding episode, EVL is successful in up to 90% of patients. If the bleeding remains uncontrolled or if there is severe early rebleeding, TIPS should be considered as the next intervention. Balloon tamponade with the Sengstaken-Blakemore tube or the placement of an esophageal stent can be used for temporary control of bleeding as a bridge to TIPS. Balloon tamponade should be limited to 24 hours as the complication rate increases significantly with longer use. Esophageal stents may be used for a longer period and are generally safer.
In patients with Child-Pugh class C cirrhosis or Child-Pugh class B with active bleeding, the placement of TIPS within the initial 24 hours from the onset of bleeding has been shown in a large multicenter RCT to be superior to medical therapy with EVL and vasoactive drugs and is associated with better control of the bleeding episode and improved survival.
In patients with cirrhosis and acute upper gastrointestinal bleeding, if varices are suspected, the patient should be started on a vasoactive drug (eg, terlipressin, octreotide) upon presentation. The source of bleeding should be determined by endoscopy within 12 hours of presentation. If varices are determined to be the source of bleeding, bleeding should be controlled with esophageal variceal ligation.
PREVENTION OF RECURRENT VARICEAL HEMORRHAGE (SECONDARY PROPHYLAXIS)
As there is a 60% chance of recurrent hemorrhage after control of the acute bleeding episode, treatment to prevent recurrent hemorrhage is mandatory. Current practice guidelines recommend a combination of nonselective β-blockers and EVL as the treatment of choice. The addition of ISMN may offer a slightly lower rebleeding rate but has the risk of increased side effects. EVL should be performed every 1 to 2 weeks until varices have been obliterated. Endoscopy should be repeated every year to screen for recurrent varices. A meta-analysis of 23 RCTs comparing combination therapy to endoscopic monotherapy shows a reduction in recurrent variceal bleeding from 37.5% for endoscopic monotherapy to 25.3% for combination treatment. There is also a modest improvement in survival. If bleeding continues to recur, TIPS is the next option. Transjugular intrahepatic portosystemic shunt is very effective in preventing recurrent hemorrhage but is associated with an increased risk of hepatic encephalopathy. Surgically performed shunts are still an option in a few centers, but their use has declined significantly with the availability of TIPS. Variceal bleeding by itself is not an indication for liver transplantation.
Gastric varices account for 10% to 15% of variceal bleeds and are associated with a higher rate of rebleeding. They occur more commonly in patients with extra-hepatic portal and/or splenic vein obstruction (eg, can be found in patients with chronic pancreatitis). Gastric varices can be divided into two types, those that are contiguous with esophageal varices (GOV1) and those that are located in the fundus of the stomach (GOV2, IGV1) or elsewhere in the stomach (IGV2). GOV1 varices are treated with EVL or pharmacologic therapy, similar to esophageal varices. The isolated gastric varices are best treated via endoscopic injection of a cyanoacrylate glue. Side effects of glue installation include fever, sepsis, retroperitoneal abscess formation and embolization. For failures of endoscopic treatment, control of hemorrhage by TIPS is successful in 90% of cases. Urgent TIPS should be considered in any patient with massive hemorrhage from gastric varices or early recurrent hemorrhage after failure of endoscopic therapy.
PORTAL HYPERTENSIVE GASTROPATHY
As seen on endoscopy, portal hypertensive gastropathy is characterized by erythema of the gastric mucosa in a mosaic like pattern with mucosal congestion and dilated capillaries and venules in the mucosa and submucosa of the stomach. It is present in more than half of patients with cirrhosis and portal hypertension and usually presents as a chronic anemia.
Hemorrhage from portal hypertensive gastropathy accounts for about 8% of gastrointestinal hemorrhage in patients with cirrhosis and is usually mild and self-limited. Nonselective β-blockers are the treatment of choice for prevention of recurrent hemorrhage. In patients with more massive bleeding requiring transfusions or in whom medical therapy has failed, TIPS should be considered.
Patients with portal vein thrombosis as the cause of portal hypertension should be evaluated for inherited and acquired thrombophilic factors, paroxysmal nocturnal hemoglobinuria, autoimmune disorders and myeloproliferative neoplasia. This is best managed in conjunction with a hematologist. For patients with acute primary thrombosis of the portal vein and/or the splanchnic venous circulation, anticoagulation is safe and recommended. Low molecular weight heparin and vitamin K antagonists are the treatment of choice. There is limited data on the use of long-term anticoagulation but it is probably safe.
Ascites is the pathologic accumulation of fluid within the peritoneal cavity. The most common cause of ascites is cirrhosis, which accounts for approximately 80% of cases. Other common causes include malignancy and congestive heart failure. Approximately 5% of patients with ascites have “mixed ascites” defined as ascites formation from two or more causes.
Ascites represents both the most common complication of portal hypertension and the leading cause for hospitalization in cirrhotic patients. Within 10 years after the diagnosis of compensated cirrhosis, about 50% of patients will have developed ascites. Approximately 15% of patients with cirrhosis die within 1 year of forming ascites, and 50% die within 5 years.
PATHOPHYSIOLOGY OF ASCITES
In patients with cirrhosis, progressive portal hypertension leads to the activation of endogenous vasoconstrictors and retention of sodium and water which then increases renal vasoconstriction. Cirrhotic vasodilation results in effective volume depletion. This is sensed as reduced pressure at the carotid and renal baroreceptors and activates sodium-retaining neurohumoral mechanisms. These mechanisms include the renin-angiotensin-aldosterone system, sympathetic nervous system and antidiuretic hormone. The net effect is avid sodium and water retention even though extracellular sodium stores and plasma volume are increased. Patients with ascites and urinary sodium below 10 mEq/d have a mean survival as low as 5 to 6 months in comparison to those who have a higher rate of sodium excretion. Similarly, the degree of water retention parallels the severity of cirrhosis. The degree of hyponatremia, as a result of increased antidiuretic hormone secretion, correlates with worsening survival. Over time, the expanded plasma volume and resulting lymph formation, in combination with decreased oncotic pressure from hypoalbuminemia, results in fluid retention within the peritoneal cavity.
EVALUATION AND DIAGNOSIS OF ASCITES
Patients with ascites typically report progressive abdominal distension that may be associated with abdominal discomfort, but may also be painless. The majority of patients with cirrhosis severe enough to cause ascites formation have stigmata of cirrhosis on physical examination, such as spider angioma, palmar erythema and abdominal wall collaterals.
Confirming ascites with physical examination can be challenging if the patient is obese or does not have a large amount of ascitic fluid. The most helpful physical sign is flank dullness, which is observed when there is at least 1500 mL of ascitic fluid in the abdomen. If no flank dullness is present, the patient has less than a 10% chance of having ascites. When flank dullness is observed, one should test for “shifting dullness,” which has 83% sensitivity and 56% specificity in detecting ascites. Examination of the jugular veins should be performed since an elevated jugular venous pressure suggests ascites from heart failure or constrictive pericarditis. An abdominal ultrasound confirms that ascitic fluid is present and can determine where a diagnostic paracentesis can be safely performed. Ultrasonography is also a safe and cost-effective modality to evaluate the liver parenchyma for evidence of cirrhosis or malignancy as well as to check the patency of the portal and hepatic veins.
A diagnostic paracentesis with appropriate ascitic fluid analysis is a quick and cost-effective method to determine the etiology of ascities and should be performed in the initial evaluation of all patients with new-onset or recurrent ascites or patients hospitalized with ascites. Infected ascitic fluid may cause or exacerbate complications of cirrhosis such as encephalopathy, fever, or renal insufficiency (Table 160-2). Abdominal paracentesis should not be delayed in the evaluation of patients with suspected spontaneous bacterial peritonitis (SBP) as it has been shown that mortality increases by 3.3% per hour of delay in performing paracentesis.
TABLE 160-2Indications for Abdominal Paracentesis in a Patient with Ascites from Cirrhosis Admitted to the Hospital ||Download (.pdf) TABLE 160-2 Indications for Abdominal Paracentesis in a Patient with Ascites from Cirrhosis Admitted to the Hospital
|New onset ascites |
|At the time of admission to the hospital |
|Clinical deterioration (at any time during admission) |
Mental status change
|Laboratory abnormalities that may indicate infection |
|Gastrointestinal bleeding |
Complications of abdominal paracentesis are rare. The most common complication is leak of ascitic fluid, which may occur in up to 5% of patients. Leaks typically arise when a proper Z-track technique has not been used. More serious complications such as severe hemorrhage and infection have been found to occur less than 1% of the time. Death due to paracentesis is extremely rare.
The routine administration of blood products (fresh frozen plasma and/or platelets) in patients with cirrhosis is not recommended. Blood products, such as FFP and platelets, should be reserved for patients with clinically evident disseminated intravascular coagulation or clinically evident hyperfibrinolysis. Patients with hyperfibrinolysis may be treated with aminocaproic acid or intravenous tranexamic acid. In patients with disseminated intravascular coagulation, platelets, and in some cases, fresh frozen plasma may be given prior to paracentesis.
Initial tests that should be performed on the ascitic fluid include the gross appearance of the fluid, cell count and differential, total protein concentration, and albumin concentration. Serum albumin should be obtained so that a serum-to-ascites albumin gradient determination (SAAG) can be calculated. Culture of ascitic fluid should be sent in patients admitted to the hospital with ascites as well as patients with signs of decompensation such as fever, abdominal pain, azotemia, acidosis, or confusion. Many laboratories save an aliquot of fluid in case further testing is necessary.
The gross appearance of the ascitic fluid can range from clear fluid typically seen in the setting of cirrhosis, turbid or cloudy fluid in the setting of infection, milky fluid in the setting of chylous ascites, and bloody fluid in the setting of malignancy or a traumatic paracentesis.
The SAAG is the most helpful test to identify the presence of portal hypertension. The SAAG is calculated by subtracting the ascitic fluid albumin value from the serum albumin value, obtained on the same day. The presence of a gradient ≥1.1 g/dL indicates that the patient has portal hypertension as the cause of ascites with 97% accuracy. In patients with cirrhosis and ascites, the SAAG reflects the degree of sinusoidal hypertension as it is assumed that a SAAG greater than 1.1 is equal or exceeds a sinusoidal pressure of 12 mm Hg. The SAAG is not specific to ascites due to cirrhosis, but will be elevated with any disorder that leads to portal hypertension. Patients with portal hypertension plus a second cause of ascites will also have a SAAG ≥1.1 g/dL. Importantly, the SAAG will remain accurate despite fluid infusion and diuretic use.
The cell count with differential is the most helpful test performed on ascitic fluid to evaluate for infection. It should be ordered with every paracentesis, as ascitic fluid infection is a potentially reversible cause of death in patients with cirrhosis and ascites. The sample should be sent in a tube containing an anticoagulant to avoid clotting. The white blood cell and neutrophil count need to be corrected in patients with bloody samples. To obtain corrected white blood cell and neutrophil counts one white blood cell should be subtracted for every 750 red blood cells and one neutrophil should be subtracted for every 250 red blood cells. Antibiotic treatment should be considered in any patient with a corrected neutrophil count ≥250/mm3.
In cirrhosis total ascitic fluid protein is usually low (<1 g/dL) and high (>2.5 g/dL) in most other causes of ascites. For example, both ascites from cirrhosis and cardiac ascites have a SAAG ≥1.1 g/dL, but in cirrhosis the total protein is <2.5 g/dL, whereas in cardiac ascites it is ≥2.5 g/dL.
Milky ascitic fluid may suggest lymphatic obstruction and should be tested for elevated triglyceride levels. Cytology should be ordered when there is a high pretest probability of peritoneal carcinomatosis. Patients with peritoneal carcinomatosis usually have a history of breast, colon, gastric, or pancreatic carcinoma. The cancer antigen 125 (CA 125) is nonspecific in the differential diagnosis of ascites and is not recommended. In patients at high risk for tuberculous peritonitis, it is appropriate to check an adenosine deminase level and AFB culture (Table 160-3).
TABLE 160-3Analysis of Ascitic Fluid ||Download (.pdf) TABLE 160-3 Analysis of Ascitic Fluid
|Routine analysis |
Cell count and differential
|Optional tests (when there is suspicion of infection) |
Culture (in blood culture bottles)
|Additional tests: performed as appropriate based on suspicion of underlying disease |
Triglyceride (chylous ascites)
Cytology (malignant ascites)
Amylase (pancreatic ascites)
AFB culture, Adenosine deaminase, TB smear (Tuberculous peritonitis)
|Unhelpful tests |
A diagnostic paracentesis should be performed in the initial evaluation of all patients with new-onset or recurrent ascites. Initial tests that should be performed on the ascitic fluid include the gross appearance of the fluid, cell count and differential, total protein concentration, and albumin concentration.
While there is no evidence that treatment of fluid overload in patients with cirrhosis improves survival, it has important benefits. Removing ascitic fluid volume provides important symptomatic relief to patients, including less abdominal discomfort and shortness of breath as well as improved mobility and appetite. Removal of fluid reduces the risk of cellulitis and abdominal wall hernia formation. It also concentrates ascitic fluid opsonins, which may reduce the risk of spontaneous bacterial peritonitis.
The treatment of ascites in patients with cirrhosis includes abstinence from alcohol, sodium restriction and diuretic therapy. In addition, patients with tense ascites should be treated with large-volume therapeutic paracenteses unless they have SBP, as it may precipitate renal injury. Removal of less than 5 L of fluid does not appear to have hemodynamic or hormonal consequences and is more rapid than diuretic therapy for ascitic fluid removal. For paracenteses over 5 L an albumin infusion of 6 to 8 g/L of fluid removed can be given and has been shown to have a survival advantage. The correct identification of the etiology of ascites is critical because patients with a low SAAG (<1.1 g/dL), such as ascites from peritoneal carcinomatosis, do not respond to sodium restriction and diuretic therapy.
The formation of ascitic fluid in a patient with portal hypertension is the result of avid renal retention of sodium and water. Therefore, a mainstay in the treatment of ascites is to restrict sodium intake. All patients with ascites should have sodium intake restricted to 88 mEq (2000 mg) per day. More stringent sodium restriction is not recommended because it is generally not tolerated, has poor compliance and may worsen malnutrition in patients with cirrhosis. Education about the importance of dietary sodium restriction is essential to the management of patients with portal hypertension related ascites as fluid loss and weight change are directly related to sodium balance.
Routine fluid restriction is not recommended in patients with cirrhosis and ascites. The chronic hyponatremia in patients with cirrhosis is rarely problematic and fluid restriction may worsen thirst and be uncomfortable for patients. Fluid restriction should be limited to patients with neurologic symptoms that may be due to severe hyponatremia (<120 mEq/L), which is an uncommon finding (1% in one series). The use of vaptans (vasopressin antagonists) in the treatment of severe hyponatremia in patients with cirrhosis is controversial and without clear evidence of a beneficial effect.
The majority of patients with cirrhosis and ascites will need diuretic therapy in addition to salt restriction to avoid fluid retention. The usual diuretic regimen consists of single morning doses of oral spironolactone and oral furosemide, which promote natruesis through different mechanisms. The starting doses are 100 mg of spironolactone and 40 mg of furosemide; this ratio generally maintains normokalemia. The doses of both oral diuretics can be increased every 3 to 5 days maintaining the 100 mg: 40 mg ratio to a maximum of 400 mg/d of spironolactone and 160 mg of furosemide. Diuretics should be initiated with a diuresis goal of 1 L/d. Spot urine sodium to potassium concentration greater than one indicates that a patient has effective aldosterone blockade and should respond to sodium restriction. All diuretics should be discontinued if there is severe hyponatremia (serum sodium concentration <120 mmol/L), progressive renal failure, worsening hepatic encephalopathy, or incapacitating muscle cramps. In addition, furosemide should be stopped if there is severe hypokalemia (<3 mmol/L) and aldosterone antagonists should be stopped if patients develop severe hyperkalemia (serum potassium >6 mmol/L). In hospitalized patients, diuretics should also be withheld in the setting active gastrointestinal bleeding, hepatic encephalopathy or renal dysfunction. Unlike patients with cardiac ascites, patients with cirrhotic ascites should not be treated with intravenous diuretics as this may lead to azotemia. The complete resolution of clinically apparent ascites is not a prerequisite for discharge.
Certain medications should be avoided or used with caution in patients with cirrhosis and ascites. In patients with cirrhosis arterial blood pressure independently predicts survival. Drugs that inhibit vasoconstrictors, such as angiotensin converting enzyme inhibitors and angiotensin receptor blockers should be avoided or used with caution because of the increased risk of renal impairment. Although propranolol has been shown to prevent variceal hemorrhage in patients with large varices, in patients with refractory ascites, β-blockers may adversely affect the patient. In patients with advanced cirrhosis, the risks versus benefits must be carefully weighed in each patient. Prostaglandin inhibitors, such as nonsteroidal anti-inflammatory drugs, should be avoided in patients since they can reduce urinary sodium excretion, lead to azotemia and may precipitate upper gastrointestinal bleeding in the setting of cirrhosis. In patients with cirrhosis and ascites, aminoglycosides alone or in combination with other antibiotics should be avoided in the treatment of bacterial infections because they are associated with a high incidence of nephrotoxicity. In addition, in hospitalized patients with cirrhosis and renal failure the use of contrast media should be used with caution.
Approximately 10% of patients with ascites due to cirrhosis develop diuretic-resistant ascites, defined as refractory ascites. Refractory ascites in patients with cirrhosis is present when at least one of the following criteria is met: an inability to mobilize ascites despite confirmed adherence to the dietary sodium restriction and the administration of maximum tolerable doses of oral diuretics (400 mg/d of spironolactone and 160 mg/d of furosemide); rapid reaccumulation of fluid after therapeutic paracentesis; the development of diuretic-related complications, such as progressive azotemia, hepatic encephalopathy, or progressive electrolyte imbalances. In hospitalized patients spot urine sodium to potassium ratio is an efficient method to determine compliance and efficacy. A urine sodium greater than urine potassium with weight loss indicates the patient is diuretic responsive and adherent to the sodium restriction; a urine sodium less than urine potassium without weight loss is diuretic resistant at the current doses; a urine sodium greater than urine potassium without loss indicates that the patient is diuretic responsive, but not adherent to the sodium restriction. It is also critical to differentiate refractory ascites from causes of ascites such as malignant ascites or the Budd Chiari syndrome (hepatic vein thrombosis), which may be determined through ascitic fluid analysis and an abdominal ultrasound with Doppler.
The first step in the management of refractory ascites is to discontinue medications that decrease systemic blood pressure and lead to renal vasoconstriction, such as angiotensin converting enzyme inhibitors, angiotensin receptor II blockers, and nonsteroidal anti-inflammatory drugs. Although many patients with cirrhosis are on β-blockers, such as propranolol, to decrease the risk of variceal bleeding, the risks versus benefits of β-blockers must be weighed carefully in each patient. β-Blockers should be discontinued in patients with refractory ascites if the systemic blood pressure is less than 90 mm Hg, if hyponatremia (<130 mEq/L) is present, or if there is acute kidney injury. Oral midodrine, an oral vasopressor, which often increases blood pressure in advanced cirrhosis, may theoretically convert diuretic-resistant patients back to diuretic sensitive. Midodrine may be started at 5 mg orally three times daily with the dose adjusted by 2.5 mg every 24 hours up to a maximal dose of 17.5 mg to achieve a mean arterial pressure greater than 82 mm Hg.
Therapeutic options for patients who fail noninvasive treatments include serial therapeutic large-volume paracenteses (LVPs), transjugular intrahepatic portosystemic shunt, and liver transplantation. Liver transplantation is primarily based on the patient’s MELD (model for end stage liver disease) score but should not be delayed in patients with refractory ascites as 21% of patients with refractory ascites die within 6 months. Serial paracenteses of 4 to 6 L per session may be effective for symptomatic relief. The use of albumin replacement in LVP to prevent circulatory dysfunction after paracenteses is controversial. Based on the available data, for paracenteses larger than 5 L, albumin (6-8 g/L of fluid removed) may be administered either during or immediately after the procedure.
Transjugular intrahepatic portosystemic stent-shunt (TIPS) reduces portal hypertension and decreases the development of cirrhotic ascites. There is increasing evidence that TIPS is more effective than large-volume paracentesis in controlling ascites and may be associated with a survival advantage. As an invasive procedure, TIPS should only be considered in carefully selected patients with diuretic-resistant ascites intolerant of repeated large-volume paracentesis or patients requiring very frequent paracentesis (eg, weekly). Patients with refractory ascites who are not good candidates for TIPS include those with Child-Pugh class C cirrhosis, a high MELD score (>18), alcoholic hepatitis, congestive heart failure, a history of severe, spontaneous hepatic encephalopathy or the absence of a caregiver in the home. Echocardiograms are typically performed to screen for heart failure prior to TIPS placement. Patients with cirrhosis and ascites usually have ejection fractions of 70% to 75% due to hyperdynamic circulation. A baseline ejection fraction of 60% is a usual minimum cutoff prior to TIPS because central pressure usually increases after TIPS and cardiac function can deteriorate.
Hepatic hydrothorax is defined as the presence of a pleural effusion in a patient with cirrhosis and ascites in the absence of other causes. Hepatic hydrothorax occurs in approximately 5% to 10% of patients with cirrhosis and ascites. The development of hepatic hydrothorax results from the passage of ascites from the peritoneal cavity into the pleural cavity through small diaphragmatic defects during the negative intrathoracic pressure generated during inspiration. The right hemidiaphragm is more susceptible to diaphragmatic defects and hepatic hydrothorax develops on the right side in approximately 73% to 85% of patients. Hepatic hydrothorax usually presents with dyspnea, a nonproductive cough, pleuritic chest pain, and hypoxemia. Patients with suspected hepatic hydrothorax should undergo thoracentesis with testing of the pleural fluid as well as additional imaging including a chest computed tomographic scan and echocardiogram to confirm the diagnosis and exclude other causes of the effusion. Pleural effusions from hepatic hydrothorax are transudative in nature; however, the protein concentration of the pleural fluid is usually higher than that of ascitic fluid due to the differences in hydrostatic forces between the abdomen and chest. If the diagnosis is uncertain, an intraperitoneal injection of technetium-radiolabeled sulfur colloid into the abdomen can be performed shortly after therapeutic thoracentesis to detect rapid passage of isotope into the chest cavity during reaccumulation.
Patients who are severely symptomatic from a large effusion should undergo a therapeutic thoracentesis. Usually no more than 2 L of fluid are removed because of the risk of pulmonary edema and hypotension. After thoracentesis, patients should be on a sodium restricted diet (<88 mEq or 2000 mg daily) and diuretics to prevent reaccumulation of fluid. Chest tubes are contraindicated in the treatment of hepatic hydrothorax as they can result in massive protein and electrolyte depletion, infection, renal failure, and bleeding, and may result in rapid deterioration or death. Spontaneous bacterial empyema (SBEM), is defined as the lack of evidence of pneumonia on chest imaging study and a positive pleural fluid culture and a polymorphonuclear leukocyte count (PMN) cell count >250 cells/mm3 or negative pleural fluid culture and a PMN cell count >500 cells/mm3. Spontaneous bacterial empyema has been reported in 13% to 16% of patients with hepatic hydrothorax. Spontaneous bacterial empyema should be treated with intravenous antibiotics used for SBP (eg, ceftriaxone 2 g every 24 hours) and may be tailored based on culture results. A repeat thoracentesis may be performed to document a patient’s response to treatment.
Patients with refractory hydrothorax, defined as a persistent hydrothorax despite a sodium-restricted diet and diuretic therapy, may initially be managed with repeated thoracentesis every 2 to 3 weeks for symptom control. Transjugular intrahepatic portosystemic shunt is the second line treatment and may be recommended in patients with a Child-Pugh score <13 who are younger than 70 years old and do not have clinically significant hepatic encephalopathy. Pleurodesis or thorascopic repair of the diaphragmatic defects are technically difficult and have had variable results, but may be considered in patients with no other therapeutic options. Liver transplantation is the definitive treatment for appropriate candidates.
SPONTANEOUS BACTERIAL PERITONITIS (SBP)
Spontaneous bacterial peritonitis is defined by the presence of an elevated ascitic fluid absolute polymorphonuclear leukocyte count (PMN) count (>250 cells /mm3) or a positive culture without an evident intra-abdominal, surgically treatable source of infection. Spontaneous bacterial peritonitis often presents with fever, abdominal pain, or altered mental status, but patients can also be asymptomatic. A diagnostic paracentesis must be performed to diagnose or exclude SBP. Therefore, all patients hospitalized with ascites should undergo a diagnostic paracentesis. Patients should have a repeat paracentesis during their hospitalization if they develop clinical signs or symptoms suggesting infection. The paracentesis should be performed prior to the administration of any antibiotics. A single dose of a broad-spectrum antibiotic may inhibit culture growth in 86% of patients. Most cases of SBP have a single organism due to gut bacteria such as E. coli and Klebsiella, though streptococcal and staphylococcal infections may also occur. A positive ascitic fluid culture is not necessary for the diagnosis of SBP and culture negative, neutrophil positive ascites occurs commonly (15%-50%). Findings suggestive of a secondary peritonitis, such as perforated viscus, diverticulitis, or intra-abdominal abscess, include polymicrobial infection, anaerobes, high protein concentration (>1 g/dL), low glucose (<50 mg/dL) or high LDH (> serum upper limit of normal). Patients with secondary bacterial peritonitis should undergo abdominal computed tomography (CT) scanning and surgical evaluation as indicated.
Broad-spectrum therapy is warranted in patients with suspected SBP until the results of sensitivity testing has returned. The infection-related mortality from SBP in the absence of renal failure or shock is low, but up to 82% in patients with cirrhosis and SBP-associated septic shock. Antibiotics should be initiated immediately after diagnostic paracentesis, especially for patients who have developed septic shock. One series showed an adjusted odds ratio for mortality of 1.9 for every hour delay in administrating antimicrobial therapy. β-Blockers use among patients with SBP has been associated with increased risk of the hepatorenal syndrome and a probable increased mortality. Therefore, β-blockers should be discontinued in a hospitalized patient with SBP.
Uncomplicated SBP should be treated with a third-generation cephalosporin, such as cefotaxime. Intravenous cefotaxime 2 g every 8 hours produces excellent ascitic fluid penetration. Lower doses can be used in patients with impaired renal function. The main adverse drug reaction of cefotaxime is rash, which occurs in approximately 1% of patients. Levofloxacin may be used for patients with a penicillin allergy, although it has less penetration into ascitic fluid than cefotaxime. Oral ofloxacin (400 mg twice per day) may also be considered for SBP treatment in patients without shock, vomiting, or a serum creatinine greater than 3 mg/dL. Fluoroquinolones, however, should not be used in a patient who had been receiving a fluoroquinolone for SBP prophylaxis as resistance to the antibiotic may have developed. The choice of antibiotics for treating SBP should also take into account local resistance patterns and recent antibiotic use. Nephrotoxic antibiotics should be avoided because the underperfused kidneys in cirrhosis are very sensitive to injury.
In patients suspected of having SBP antibiotics should be initiated immediately after diagnostic paracentesis. First line therapy is typically with a third-generation cephalosporin, but the choice of antibiotics for treating SBP should also take into account local resistance patterns and recent antibiotic use.
In most patien.ts, including those who are bacteremic, 5 days of therapy is usually sufficient and antibiotics can be discontinued without a routine repeat paracentesis if the patient has clinically improved. However, if after 5 days of therapy, fever or pain persists, paracentesis is repeated, and the decision to continue or discontinue antibiotics is determined by the PMN response. If the PMN count is <250 cells/mm3, treatment is stopped; if the PMN count is elevated, but less than the pretreatment value, antibiotics are continued for another 48 hours, and paracentesis is repeated. If the PMN count is greater than the pretreatment value, a search for secondary bacterial peritonitis is initiated. Only patients who grow an unusual organism (eg, pseudomonas), an organism resistant to standard antibiotic therapy, or an organism routinely associated with endocarditis (eg, Staphylococcus aureus or viridans group streptococci) are initially considered for longer treatment.
Renal failure develops in 30% to 40% of patients with SBP and is a major cause of death. This risk may be reduced with an infusion of intravenous albumin (1.5 g/kg body weight within 6 hours of diagnosis and 1.0 g/kg on day 3). Albumin infusion should be given if the creatinine is >1 mg/dL, the blood urea nitrogen is >30 mg/dL, or if the total bilirubin is >4 mg/dL.
It is reasonable to give empiric therapy to patients with alcoholic hepatitis who present with fever and/or leukocytosis, but have a PMN count <250 cells/mm3. Empiric therapy can be discontinued after 48 hours if ascitic fluid, blood, and urine cultures remain negative.
Recurrence of SBP has been reported to be 69% in 1 year. Risk factors for the development of SBP include ascitic fluid protein concentration <1.0, variceal hemorrhage, or a prior episode of SBP. The use of antibiotic prophylaxis for patients at high risk for SBP decreases the risk of bacterial infection and mortality. However, the use of antibiotic prophylaxis does select for resistant flora, which can result in recurrent infection. Therefore, antibiotic prophylaxis should be limited to patients with strict indications. These include an ascitic fluid total protein less than 1.5 g/dL with impaired renal function (creatinine ≥1.2, BUN ≥25 or serum Na ≤130) or liver failure (Child score ≥9 and bilirubin ≥3), patients with a previous episode of SBP, or in patients with cirrhosis and gastrointestinal bleeding. The antibiotic regimen used for SBP prophylaxis depends on the indication. For patients with an ascitic fluid total protein less than 1.5 g/dL and with impaired renal function (creatinine ≥1.2, BUN ≥25 or serum Na ≤130) or liver failure (Child score ≥9 and bilirubin ≥3) or patients with a previous episode of SBP, prolonged therapy with norfloxacin 400 mg/d, orally, is preferred. Ciprofloxacin 750 mg/wk or trimethoprim-sulfamethoxazole (800 mg sulfamethoxazole and 160 mg trimethoprim, daily, orally) are acceptable alternatives if norfloxacin is not tolerated. In patients with cirrhosis and gastrointestinal bleeding, intravenous ceftriaxone 1 g daily is initiated and can be switched to oral norfloxacin (400 mg orally twice daily) for a total course of 7 days once bleeding has been controlled and the patient is stable.
In addition to antibiotic prophylaxis, general measures may be taken to prevent SBP in hospitalized patients with cirrhosis and ascites. The early recognition and aggressive treatment of localized infections (eg, cystitis and cellulitis) as well as the judicious use of urinary catheters can prevent bacteremia and SBP. Diuretic therapy, if not contraindicated, concentrates ascitic fluid and raises opsonic activity, which may help prevent SBP. Protein pump inhibitors have been associated with an increased risk of SBP and should be restricted to patients with a clear indication for their use (Figure 160-3).
Approach to management of ascites.
The hepatorenal syndrome is defined as the occurrence of renal failure in a patient with cirrhosis and ascites in the absence of other causes of renal failure, shock or hypovolemia. Hypovolemia is excluded by the absence of response defined as no sustained improvement of renal function (creatinine decreasing to <133 μmol/L) following at least 2 days of volume expansion with intravenous albumin (1 g/kg of body weight per day up to 100 g/d) and/or the discontinuation of diuretics. Other apparent causes for acute kidney injury should be excluded including current or recent treatment with nephrotoxic drugs, and the ultrasonographic evidence of obstruction or parenchymal disease. A kidney biopsy is often helpful in excluding pre-existing renal disease, especially if liver transplantation is being considered. The diagnosis is based on an increase in serum creatinine of 0.3 mg/dL or more within 48 hours, or an increase from baseline of 50% or more within 7 days. In hospitalized patients, repeat measurements of creatinine are helpful in the early diagnosis of hepatic renal syndrome (HRS). Additional clinical criteria include urine red cell excretion of less than 50 cells per high power field (in the absence of a urinary catheter) and protein excretion less than 500 mg/d The hepatorenal syndrome occurs in approximately 20% of patients with cirrhosis and ascites at 1 year and up to 40% at 5 years and is associated with a high mortality rate. There are two forms of hepatorenal syndrome based on the rate of decline in renal function. Type 1 hepatorenal syndrome is the more serious form and is defined as at least a twofold increase in serum creatinine to a level greater than 2.5 mg/dL during a period of less than 2 weeks. Precipitating conditions include infection, especially SBP, and severe alcoholic hepatitis. The median survival for untreated type 1 HRS is 1 month. The early diagnosis and treatment of infection can reduce the risk of HRS and is associated with an improved survival. Type 2 hepatorenal syndrome is defined as renal impairment that is less severe than in patients with the type 1 form. It is important to note that diuretics do not cause hepatorenal syndrome but can lead to diuretic-induced azotemia, which improves with the cessation of therapy and fluid repletion. Patients with relative adrenal insufficiency have greater impairment of circulatory and renal function and a higher probability of type 1 HRS and severe sepsis when compared to patients with decompensated cirrhosis but normal adrenal function.
The goal of medical therapy is to improve renal function by reversing portal hypertension induced arterial vasodilation in the splanchnic circulation. In patients with HRS who are admitted to the intensive care unit, careful monitoring of urine output, fluid balance, arterial pressure and vital signs is imperative. Initially, all diuretics should be discontinued. In patients with tense ascites, paracentesis may be helpful in alleviating abdominal discomfort.
Medical therapy is aimed at improving the severely impaired circulatory function by inducing vasoconstriction of the dilated vascular bed and increasing arterial pressure. Based on results of many randomized controlled trials, the use of vasoconstrictive drugs, especially terlipressin, has been associated with improvement in up to 50% of patients. Terlipressin in combination with albumin is the treatment of choice. Terlipressin is given as an intravenous bolus of 1 to 2 mg every 4 to 6 hours, and albumin is given for 2 days as an intravenous bolus of 1 g/kg/d (100 g maximum), followed by 25 to 50 g/d until terlipressin therapy is discontinued. Contraindications to terlipressin therapy include ischemic cardiovascular diseases. Patients treated with terlipressin should be carefully monitored for development of cardiac arrhythmias or signs of splanchnic or digital ischemia. Terlipressin is currently unavailable in the United States. Alternative treatments include noradrenaline and midodrine, a selective alpha-1 adrenergic agonist, plus octreotide, a somatostatin analog, in addition to albumin infusion. Midodrine is given orally at a starting dose 7.5 mg three times daily, uptitrated to 15 mg three times per day. The midodrine dose should be uptitrated with each consecutive dose to raise the mean arterial pressure by approximately 10 to 15 mm Hg. Octreotide is either given as a continuous intravenous infusion of 50 μg/h or subcutaneously 100 to 200 mg three times daily. Albumin is given for 2 days as an intravenous bolus of 1 g/kg (100 g maximum), followed by 25 to 50 g/d until midodrine and octreotide therapy is discontinued. Norepinephrine is administered as a continuous infusion (0.5-3 mg/h) with the goal of raising the mean arterial pressure by 10 to 15 mm Hg.
Patients treated with norepinephrine, terlipressin, or octreotide are typically treated for 2 weeks. The duration may be extended, however, if after 2 weeks there is some, but not complete improvement in renal function. In patients who respond to therapy, treatment with oral midodrine to maintain higher mean arterial pressure can be continued at discharge until resolution of liver injury or liver transplantation in appropriate candidates. If a patient has no improvement in renal function after 2 weeks then medical therapy is discontinued as the outcome is usually futile. In a recent study, patients with type 1 HRS associated with infection, HRS was not reversible despite treatment with vasoconstrictive drugs in two thirds of patients. Therefore, these patients must be treated immediately with antibiotics if there is suspicion of infection.
Options for patients who fail to respond to medical therapy include TIPS and hemodialysis. The use of TIPS in patients with hepatorenal syndrome may provide short-term benefit in selected patients but data to its applicability is very limited and many of these patients have contraindications to TIPS placement. Given the risks associated with the procedure, TIPS should be limited to patients who are well enough to tolerate the procedure and are awaiting liver transplantation. In patients who fail medical therapy and are not considered candidates for TIPS, hemodialysis or continuous venous hemofiltration can be considered as treatment for severe metabolic abnormalities such as metabolic acidosis and hyperkalemia but there is very limited data as to their efficacy. Studies are currently underway investigating artificial liver support systems in the management of HRS. In appropriate candidates, liver transplantation is the treatment of choice for both type 1 and type 2 HRS, with survival rates of approximately 65% in type 1 HRS.
Hepatic encephalopathy represents a spectrum of neuropsychiatric disturbances in patients with impaired hepatic function. In patients with cirrhosis, overt hepatic encephalopathy develops in 30% to 45% of patients. Neuropsychiatric findings range from subtle abnormalities that are not apparent without specialized testing to overt coma. Important factors that determine the severity of hepatic encephalopathy include level of consciousness, cognitive function, behavioral disturbances, and neuromuscular features.
Although the exact pathogenesis of hepatic encephalopathy remains unclear, most theories suggest that the brain is exposed to toxic substances that are produced by bacterial flora, which are incompletely cleared by the compromised liver. The most well described neurotoxic substance is ammonia. The majority of patients with overt hepatic encephalopathy will have elevated arterial blood levels of ammonia, though the degree of ammonia elevation does not necessarily correlate with degree of hepatic encephalopathy. Gamma-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the central nervous system, may also play an important role in the development of hepatic encephalopathy. It has been theorized that gut bacteria produce increased endogenous benzodiazepine ligands that bind the benzodiazepine site of GABA receptors.
The generally accepted classification for hepatic encephalopathy takes into account the type of hepatic abnormality and the duration and characteristics of the neuropsychiatric manifestations. Hepatic encephalopathy may be associated with acute liver failure (type A), portosystemic shunting without intrinsic liver disease (type B), and cirrhosis (type C). Hepatic encephalopathy associated with cirrhosis is characterized as episodic, recurrent, persistent, or minimal. Episodic hepatic encephalopathy develops over a short period of time and is further classified based on whether it was precipitated or has developed spontaneously. Recurrent encephalopathy is defined as bouts of hepatic encephalopathy that occur within a time interval of 6 months or less. Patients with persistent encephalopathy exhibit continuous overt neurologic or behavioral abnormalities, which are interspersed with episodes of overt hepatic encephalopathy. Patients with minimal hepatic encephalopathy often appear asymptomatic and have subtle neuropsychiatric abnormalities that may only be detected with psychomotor or electrophysiologic testing. Patients with overt hepatic encephalopathy have signs and symptoms that can be detected clinically. The severity of overt hepatic encephalopathy is graded from I to IV. Grade I: patients have changes in behavior, mild confusion, slurred speech, and disordered sleep (both hypersomnia and insomnia); Grade II: patients have increasing lethargy and moderate confusion; Grade III: patients have marked confusion (stupor), incoherent speech, and often sleeping yet arousable; Grade IV: patients are in a coma and unresponsive to pain. In reality, it is difficult to differentiate between Grade II and Grade III hepatic encephalopathy (Table 160-4).
TABLE 160-4Hepatic Encephalopathy in Chronic Liver Disease 2014 Practice Guideline WHC and Clinical Description ||Download (.pdf) TABLE 160-4 Hepatic Encephalopathy in Chronic Liver Disease 2014 Practice Guideline WHC and Clinical Description
|WHC Including MHE ||ISHEN ||Description ||Suggested Operative Criteria ||Comment |
| Unimpaired ||No encephalopathy at all, no history of HE ||Tested and proved to be normal || |
|Minimal || ||Psychometric or neuropsychological alterations of tests exploring psychomotor speed/executive functions or neurophysiological alterations without clinical evidence of mental change ||Abnormal results of established psychometric or neuropsychological tests without clinical manifestations || |
No universal criteria for diagnosis
Local standards and expertise required
| ||Covert || || || |
|Grade I || || ||Despite oriented in time and space (see below), the patient appears to have some cognitive/behavioral decay with respect to his or her standard on clinical examination or to the caregivers ||Clinical findings usually not reproducible |
|Grade II || || ||Disoriented for time (at least three of the following are wrong: day of the month, day of the week, month, season, or year) ± the other mentioned symptoms ||Clinical findings variable, but reproducible to some extent |
| ||Overt || || || |
|Grade III || || |
Somnolence to semistupor
Responsive to stimuli
|Disoriented also for space (at least three of the following wrongly reported: country, state [or region], city, or place) ± the other mentioned symptoms ||Clinical findings reproducible to some extent |
|Grade IV || ||Coma ||Does not respond even to painful stimuli ||Comatose state usually reproducible |
Patients with mild hepatic encephalopathy (Grade I) may be managed as outpatients, provided caregivers are available to monitor for signs of worsening hepatic encephalopathy. Patients with Grade II encephalopathy may be admitted to hospital depending on the degree of lethargy and confusion. Patients with more severe hepatic encephalopathy (Grades III and IV) require hospital admission for treatment, typically in an intensive care unit as they may require intubation for airway protection.
The diagnosis of hepatic encephalopathy is largely clinical. There are no specific signs, symptoms, laboratory, or imaging tests diagnostic of hepatic encephalopathy. Therefore, it is critical to rule out other etiologies of altered mental status, such as hypoglycemia, intracranial pathology, or uremia. The history should focus on changes in mental status, including subtle changes, such as changes in sleep patterns, and impaired work or driving performance. The physical examination should look for signs of chronic liver disease and neuromuscular impairment, which include bradykinesia, hyperreflexia, rigidity, myoclonus, and asterixis. Focal neurologic deficits such as hemiplegia, hemiparesis, and seizures are not commonly observed in patients with hepatic encephalopathy and warrant further central nervous system evaluation. Although elevated arterial blood levels of ammonia are commonly seen in hepatic encephalopathy, their diagnostic value remains controversial. Ordering of ammonia levels can be helpful, however, to determine the likelihood of hepatic encephalopathy in patients where another etiology for encephalopathy is reasonably likely. In patients whom minimal encephalopathy is suspected, psychometric testing, such as the number connection test (Reitan Test), can be helpful. The NCT is a timed connect-the-numbers test. Patients without hepatic encephalopathy should finish the test in a number of seconds less than or equal to their age in years (eg, a 40-year-old patient should finish the test in 40 seconds). Electroencephalogramtesting in patients with overt hepatic encephalopathy is always abnormal, but the observed changes are not specific.
Common precipitating factors in patients with episodic hepatic encephalopathy associated with cirrhosis include gastrointestinal bleeding, infection, azotemia, hypokalemia, acute hepatitis, and sedative and diuretic drug side effects. It is critical to identify and treat any possible precipitating factors as this will often result in resolution or improvement of hepatic encephalopathy.
Gastrointestinal bleeding is the most common precipitant of episodic hepatic encephalopathy in patients with cirrhosis as a result of decreased hepatic perfusion and increased production of nitrogenous byproducts from the digestion of blood proteins. The most common infection that triggers hepatic encephalopathy in hospitalized patients is SBP. Therefore, all patients with hepatic encephalopathy and ascites should undergo a diagnostic paracentesis. If there is a high index of suspicion for infection, antibiotics should be initiated after cultures are drawn. Intravascular volume depletion results in reduced renal perfusion and increased ammonia production. Hypokalemic alkalosis also results in increased renal ammonia production. Common medications that can precipitate hepatic encephalopathy include sedatives and analgesics, especially benzodiazepines (Table 160-5).
TABLE 160-5Common Precipitants of Hepatic Encephalopathy ||Download (.pdf) TABLE 160-5 Common Precipitants of Hepatic Encephalopathy
Drug side effects
Increased ammonia production, absorption or entry into the brain
Electrolyte disturbances such as hypokalemia
Excess dietary intake of protein
Vomiting, diarrhea, hemorrhage
Large volume paracentesis
Hepatic vein thrombosis
Portal vein thrombosis
In addition to correcting precipitating factors, patients admitted to the hospital with acute, overt hepatic encephalopathy, should be treated with pharmacologic therapy to lower the blood ammonia concentration. Initial therapy is with the nonabsorbable disaccharides, lactulose or lactitol (not available in the United States). These medications theoretically increase ammonia clearance through catharsis as well as decreasing intestinal ammonia through the lowering of the colonic pH, favoring the formation of nonabsorbable NH4+ from NH3 and trapping NH4+ in the colon. Although there is limited evidence from large randomized controlled trials showing their efficacy, patients often show improvement in symptoms within hours of lactulose administration. The dose of medication should be titrated to achieve two to three soft stools per day. Typically, lactulose is given as 30 to 45 mL (20-30 g) two to four times per day. An equivalent dose of lactitol is approximately 67 to 100 g lactitol powder diluted in 100 mL of water. Lactulose and lactitol can also be given as enema in patients who are unable to take them orally. Treatment is usually well tolerated and the main side effects are abdominal cramping, diarrhea, and flatulence.
Orally administered poorly absorbed antibiotics likely improve hepatic encephalopathy by decreasing toxin production by gut flora. For patients who have not improved within 48 hours of starting lactulose or lactitol, or who cannot take lactulose or lactitol, rifaximin is the nonabsorbable antibiotic of choice for treating hepatic encephalopathy. Rifaximin is a derivative of rifamycin and has broad-spectrum activity against Gram negative-rods and Gram-positive cocci. The dose of rifaximin is 550 mg orally twice daily or 400 mg three times daily. The cost of rifaximin ($1-2000 per month) may limit its use. Neomycin, an aminoglycoside, had been used in the past, but should be avoided due to the risk of ototoxicity and renal failure. Other antibiotics, such as vancomycin and flagyl have been shown to be effective in treating hepatic encephalopathy in limited trials, but are not used commonly given the risk of neuropathy with flagyl and concerns about bacterial resistance.
Other therapies that enhance ammonia clearance include sodium benzoate, and L-ornithine L-asparate (LOLA). Sodium benzoate reduces ammonia levels by reacting with glycine to form hippurate, which is excreted by the kidneys. A recent RCT found that 5 gm twice daily resulted in improvement in encephalopathy similar to that seen with lactulose. L-ornithine L-asparate increases hepatic conversion of ammonia and has been shown to perform better than placebo at lowering plasma ammonia as well improving the hepatic encephalopathy grade. Flumazenil, a benzodiazepine receptor antagonist, has been shown to improve the hepatic encephalopathy grade, but data are conflicting and it should not be used as routine therapy. Oral branched-chain amino acids, which are available in several different formulations, improve symptoms in patients who are protein-intolerant, and can be used in patients who do not respond to lactulose, lactitol, or rifaxmin and who are severely protein-intolerant. Probiotics reduce substrate for other gut bacteria and have been shown to reduce ammonia levels and improve psychometric hepatic encephalopathy scores.
Patients hospitalized with hepatic encephalopathy may be agitated and may be a hazard to themselves or caretakers and require physical use of restraints. It is important to remember that patients with advanced liver disease are more prone to oversedation, particularly with the use of benzodiazepines. If pharmacologic treatment is needed, haloperidol is a safer option.
High dietary protein intake may be associated with hepatic encephalopathy. In theory, dietary protein results in increased nitrogenous toxin production in the gut. However, while dietary protein restriction may improve symptoms in some patients, its efficacy has been difficult to establish in randomized controlled trials. Moreover, patients with cirrhosis are often malnourished and protein restriction is associated with increased mortality. Therefore, routine protein restriction is not recommended. Nutritional support should include maintaining an energy of 35 to 40 kcal/kg/d with a protein intake of 1.2 to 1.5 g/kg/d.
Patients with recurrent hepatic encephalopathy that has resolved during admission should be continued on lactulose, lactitol, and/or rifaximin at time of discharge. Prior to discharge patients admitted with overt hepatic encephalopathy should have an assessment regarding driving risk. It is also critical to determine if patients admitted with hepatic encephalopathy have an adequate outpatient support system.
ACUTE-ON-CHRONIC LIVER FAILURE
Acute-on-chronic liver failure (ACLF) is a recently recognized syndrome characterized by acute decompensation of cirrhosis and organ/system failure and is associated with a high-short-term mortality (estimated 28-day mortality rate of 23%-74% depending on the number of organ failures). Acute decompensation refers to the development of ascites, encephalopathy, gastrointestinal hemorrhage and/or bacterial infections. Acute decompensation develops in many cirrhotic patients in the absence of any other significant feature, but its development in association with organ failure with high mortality rates led to the recognition of acute-on-chronic liver failure as a distinct clinical entity. The prevalence of acute-on-chronic liver failure in patients hospitalized with acute decompensation is 30%.
In a large multicenter European study by Yiu et al involving 392 patients, acute decompensation and a single entity for liver failure and no evidence of acute kidney failure or hepatic encephalopathy, the short-term mortality was very low. However, if there was evidence of organ failure, especially acute kidney failure or bacterial infection, the mortality rate was 15 times higher than patients with uncomplicated acute decompensation (Table 160-6). Interestingly, ACLF occurred in half of the patients in whom there was no prior history of AD or in whom AD developed within a few weeks of hospitalization. Acute-on-chronic liver failure patients were younger (<55 years), often had alcoholic cirrhosis and were less likely to have hepatitis C as the cause of cirrhosis. Common precipitating events were bacterial infection or active alcoholism. Half of the patients had kidney injury as the primary organ failure. Predictors of ACLF and ACLF related mortality were a high leukocyte count and a prior history of AD although, somewhat surprisingly, patients without a prior history of AD had a more severe form of ACLF and a higher mortality.
TABLE 160-6Etiology of Precipitating Events for All Diagnosed ACLF Patients ||Download (.pdf) TABLE 160-6 Etiology of Precipitating Events for All Diagnosed ACLF Patients
|Items ||Frequency |
|With hepatic insults (N = 180) || |
|Hepatic insults alone || |
|Flare-up or exacerbation of HBV, no. (%) ||145 (35.8) |
|Superimposed HAV or HEV infection, no. (5) ||26 (6.4) |
|Hepatotoxic drugs, no. (%) ||10 (2.5) |
|Active drinking, no. (%) ||25 (6.2) |
|Flare-up of AIH or Wilson’s disease, no. (%) ||6 (1.5) |
|More than one hepatic insult, no. (%) ||28 (6.9) |
|Mixed with extrahepatic insults || |
|Bacterial infection, no. (%) ||28 (6.9) |
|UGIB, no. (%) ||4 (1.0) |
|Extrahepatic insults alone (N = 142) || |
|Bacterial infection, no. (%) ||113 (27.9) |
|UGIB, no. (%) ||36 (8.9) |
|Surgery, no. (%) ||1 (0.2) |
|More than one extrahepatic insult, no. (%) ||8 (2.0) |
|Unknown (N = 83) ||83 (20.5) |
Acute-on-chronic liver failure may develop at any time during the course of the disease in a patient from compensated cirrhosis to a patient with long-standing cirrhosis and history of acute decompensation. The severity of acute-on-chronic liver failure correlates with the number of organ failures. The development of acute-on-chronic liver failure occurs in the setting of a systemic inflammation although in 40% of cases no precipitating event can be identified. While the pathophysiology of acute-on-chronic liver failure is not well understood, it is thought that systemic inflammation may cause acute-on-chronic liver failure through complex mechanisms that include an exaggerated inflammatory response and systemic oxidative stress to pathogen and/or alteration of tissue homeostasis to inflammation caused either by the pathogen itself or through dysfunction of tissue tolerance. Patients with acute-on-chronic liver failure have high leukocyte count and plasma-C reactive protein concentrations.
To further clarify the definition of ACLF, a division into three categories has been proposed by Jalen et al. which takes into account whether or not there is underlying cirrhosis, and whether there is a history of previous decompensation in patients with cirrhosis. Type A ACLF refers to noncirrhotic ACLF and includes as examples, patients with reactivation of hepatitis B, hepatitis A or hepatitis E, infection superimposed upon chronic hepatitis B, autoimmune hepatitis or patients with fatty liver and superimposed drug-induced liver injury. Type B ACLF is seen in patients with compensated cirrhosis who deteriorate rapidly after a major insult such as acute viral, drug or alcoholic hepatitis, infection or surgery. Type C ACLF refers to patients with a prior episode of decompensation and an acute precipitating event.
Various prognostic scores have been proposed to aid in the recognition, stratification, and management of patients with acute-on-chronic liver failure depending on whether the patient has hepatic or extrahepatic ACLF. Hepatic ACLF is precipitated by primarily hepatic insults while extrahepatic ACLF is exclusively precipitated by extrahepatic insults. The MELD score may be a better predictor for hepatic ACLF while the CLIF-SOFA score, which includes measurements of six organ systems including respiratory cardiovascular, renal, neurologic, liver and coagulation, appears to be more useful for extrahepatic organ failure. The EASL-Chronic Liver Failure consortium has recently proposed an algorithm using prognosis scores to aid in the management of patients with, or at risk for the development of, ACLF.
The general management of acute-on-chronic liver failure includes early identification and treatment of potential triggers and supportive care. Patients with acute-on-chronic liver failure should be managed in an intensive care unit for frequent monitoring and treatment of organ failure. Although not all patients with acute-on-chronic liver failure are transplant candidates, those that are should be transferred to a liver transplant center. Although data are limited, the 1-year survival after liver transplant is approximately 80%. Current therapies being explored further are extracorporeal liver support systems, bioartificial support, and stem cell therapy.
In addition to the patients’ primary care physician and/or hospitalist, treatment of these patients usually requires input from specialists in hepatology, endoscopy, interventional radiology and, occasionally, surgery. This team approach has resulted in a significant reduction in the morbidity and mortality associated with the management of the complications of cirrhosis and portal hypertension.
et al. EASL-ALEH Clinical practice guidelines: Non-invasive tests for evaluation of liver disease severity and prognosis. J Hepatol
L. Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies. J Hepatology. 2006;44:217.
et al. Competing risks and prognostic stages of cirrhosis: a 25-year inception cohort study of 494 patients. Aliment Pharmacol Ther
R. Expanding consensus in portal hypertension. Report of the Baveno VI consensus workshop: stratifying risk and individualizing care for portal hypertension. J Hepatol
et al Early use of TIPS in patients with cirrhosis and variceal bleeding. N Engl J Med
et al. Prevention and management of gastroesophageal varices and variceal hemorrhage in cirrhosis (AASLD and ACG practice guideline). Hepatol. 2007;46:922.
et al. Meta-analysis: combination endoscopic and drug therapy to prevent variceal rebleeding in cirrhosis. Ann Intern Med
MA. Portal Hypertension and Variceal Hemorrhage. In: Greenberger
R (eds). Current Diagnosis and Treatment: Gastroenterology, Hepatology and Endoscopy. New York, NY: McGraw Hill Education Medical; 2015 (In press).
et al. Beta blockers to prevent gastroesophageal varices in patients with cirrhosis. N Engl J Med
et al. Liver stiffness is associated with risk of decompensation, liver cancer, and death in patients with chronic liver disease: a systematic review and meta-analysis. Clin Gastroenterol Hepatol
J. Renal function abnormalities, prostaglandins, and effects of nonsteroidal anti-inflammatory drugs in cirrhosis with ascites. An overview with emphasis on pathogenesis. Am J Med
infusion in patients undergoing large-volume paracentesis: a meta-analysis of randomized trials. Hepatology
EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis. J Hepatol
et al. Delayed paracentesis is associated with increased in-hospital mortality in patients with spontaneous bacterial peritonitis. Am J Gastroenterol
et al. Paracentesis is associated with reduced mortality in patients hospitalized with cirrhosis and ascites. Clin Gastroenterol Hepatol
et al. Cardiovascular, renal, and neurohumoral responses to single large-volume paracentesis in patients with cirrhosis and diuretic-resistant ascites. Am J Gastroenterol
B. Management of adult patients with ascites due to cirrhosis: an update (AASLD practice guideline). Hepatology
BA, AASLD. Introduction to the revised American Association for the Study of Liver Diseases Practice Guideline management of adult patients with ascites due to cirrhosis 2012. Hepatology
JG. Diuresis increases ascitic fluid opsonic activity in patients who survive spontaneous bacterial peritonitis. J Hepatol
et al. The serum-ascites albumin
gradient is superior to the exudate-transudate concept in the differential diagnosis of ascites. Ann Intern Med
et al. Effect of intravenous albumin
on renal impairment and mortality in patients with cirrhosis and spontaneous bacterial peritonitis. N Engl J Med
SPONTANEOUS BACTERIAL PERITONITIS (SBP)
L. Antibiotics for spontaneous bacterial peritonitis in cirrhotic patients. Cochrane Database Syst Rev. 2009;CD002232.
J, Ruiz del Arbol
et al. Norfloxacin
in the prophylaxis of infections in patients with advanced cirrhosis and hemorrhage. Gastroenterology
et al. Nonselective β blockers increase risk for hepatorenal syndrome and death in patients with cirrhosis and spontaneous bacterial peritonitis. Gastroenterology
et al. The effect of selective intestinal decontamination on the hyperdynamic circulatory state in cirrhosis. A randomized trial. Ann Intern Med
et al. Short-course versus long-course antibiotic treatment of spontaneous bacterial peritonitis. A randomized controlled study of 100 patients. Gastroenterology
et al. Effect of intravenous albumin
on renal impairment and mortality in patients with cirrhosis and spontaneous bacterial peritonitis. N Engl J Med
BA. Spontaneous bacterial peritonitis. Clin Infect Dis