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1802 CLINICAL REVIEWS nature publishing group

Management and Treatment of Patients With and : Recommendations From the

REVIEW REVIEW Department of Veterans Affairs C Resource Center Program and the National Program

G u a d a l u p e G a r c i a - T s a o , M D1 , 2 , J o s e p h L i m , M D1 , 2 a n d M e m b e r s o f t h e V e t e r a n s A @ airs Hepatitis C Resource Center Program

Cirrhosis represents the end stage of any chronic . Hepatitis C and alcohol are currently the main causes of cirrhosis in the United States. Although initially cirrhosis is compensated, it eventually becomes decompensated, as defi ned by the presence of , variceal hemorrhage, , and/ or . These management recommendations are divided according to the status, compensated or decompensated, of the cirrhotic patient, with a separate section for the , diagnosis, and management of (HCC), as this applies to patients with both compensated and decompensated cirrhosis. In the compensated patient, the main objective is to prevent variceal hemorrhage and any practice that could lead to decompensation. In the decompensated patient, variceal hemorrhage and spontaneous bacterial are severe complications that require hospitalization. Hepatorenal is also a severe of cirrhosis but one that usually occurs in patients who are already in the hospital and, as it represents an extreme of the hemodynamic alterations that lead to ascites formation, it is placed under treatment of ascites. Recent advances in the pathophysiology of the complications of cirrhosis have allowed for a more rational management of cirrhosis and also for the stratifi cation of patients into different risk groups that require different management. These recommendations are based on evidence in the literature, mainly from randomized clinical trials and meta-analyses of these trials. When few or no data exist from well-designed prospective trials, emphasis is given to results from large series and consensus conferences with involvement of recognized experts. A rational management of cirrhosis will result in improvements in quality of life, treatment adherence, and, ultimately, in outcomes.

SUPPLEMENTARY MATERIAL is linked to the online version of the paper at http://www.nature.com/ajg

Am J Gastroenterol 2009; 104:1802–1829; doi:10.1038/ajg.2009.191; published online 19 May 2009

INTRODUCTION sign of portal hypertension detected by Cirrhosis represents the end stage of any chronic . (, caput medusae), laboratory investigation (even Hepatitis C and alcohol are currently the main causes of cir- a subtle decrease in count, such as a count < 175,000 / rhosis in the United States. Two major result from mm 3), or by imaging studies (colloid shi% o n t h e l i v e r – s p l e e n cirrhosis, namely portal hypertension and hepatic insu - scan; a nodular surface, collaterals, and splenomegaly seen on ciency. In addition, peripheral and splanchnic vasodilatation computed tomography scan or ) is indicative of the with the resulting hyperdynamic circulatory state is typical of presence of cirrhosis. Moreover, even subtle indicators of liver cirrhosis and portal hypertension. ! e hyperdynamic circula- insu ciency ( levels < 3.8 mg / dl or INR, international tory state is characterized by low arterial pressure, high cardiac normalized ratio, > 1.3) can suggest the presence of cirrhosis. output, and decreased peripheral . Cirrhosis can remain compensated for many years before the In a patient with any , $ nding a palpa- development of a decompensating event (1) . Decompensated ble le% lobe of the liver (hard and nodular) and a small right cirrhosis is marked by the development of any of the follow- lobe span suggests the presence of cirrhosis. Similarly, any ing complications: jaundice, variceal hemorrhage, ascites, or

1 Department of Veterans Affairs Medical Center , West Haven, Connecticut , USA and 2 Yale University New Haven, Connecticut , USA . Correspondence: Guadalupe Garcia-Tsao, MD, CT-VA Healthcare System, One Gilbert Street, TAC, room no. S241B, New Haven, Connecticut 06510 USA. E-mail: [email protected] Received 29 November 2008; accepted 16 February 2009

The American Journal of VOLUME 104 | JULY 2009 www.amjgastro.com Management and treatment of patients with cirrhosis and portal hypertension 1803

encephalopathy (1) . Jaundice results from hepatic insu ciency ! e two goals in the management of compensated cirrhosis and, other than , there is no speci$ c ther- are (i) treatment of the underlying liver disease (e.g., hepatitis C apy for this complication. However, it is important to recognize or B, alcohol, non-alcoholic ), and (ii) prevention / and treat superimposed entities (e.g., , , early diagnosis of the complications of cirrhosis. ! e treatment drug ), which may contribute to the development of the underlying liver disease is beyond the scope of these rec- of jaundice. ! e other complications of cirrhosis occur mainly ommendations. ! e main recommendations speci$ c to patients as a consequence of portal hypertension and hyperdynamic with newly diagnosed cirrhosis are screening for varices and circulation. Gastroesophageal varices result almost solely from HCC (see “ Screening, diagnosis, and management of HCC” ). REVIEW portal hypertension, although con- tributes to variceal growth and hemorrhage. Ascites results Screening for gastroesophageal varices and primary from sinusoidal hypertension and retention, which is, prophylaxis of variceal hemorrhage in turn, secondary to vasodilatation and activation of neuro- An esophagogastroduodenoscopy (EGD) should be performed humoral systems. (HRS) results from once the diagnosis of cirrhosis is established (4 – 6) . ! e objective severe peripheral vasodilatation, which leads to renal vasocon- of EGD is to detect the presence /size of varices for determining striction. (HE) is a consequence of whether the patient should receive for prevention of shunting of through portosystemic collaterals (as a result $ rst variceal hemorrhage (primary prophylaxis). of portal hypertension), brain edema (cerebral vasodilatation), Gastroesophageal varices are present in ~50 % of cirrhotic and hepatic insu ciency. patients. ! eir presence correlates with the severity of liver A simple way of assessing the severity of cirrhosis is by deter- disease; although only 40% of CTP class A patients have mining the Child – Turcotte – Pugh (CTP) class (Supplementary varices, they are present in 85 % of CTP class C patients (7) . Table 1 online ). Patients who belong to CTP class A are com- Patients with gastroesophageal varices develop variceal hem- pensated and those in CTP classes B and C are decompensated. orrhage at the rate of 12 – 15 % per year. ! e mortality rate ! e development of hepatocellular carcinoma (HCC) can with each episode of variceal hemorrhage is approximately lead to decompensation and, conversely, decompensated cir- 15– 20 % . ! erefore, one of the main preventive measures for rhosis is an independent predictor of death in HCC; therefore, the patient with compensated cirrhosis is the prevention of HCC should be considered as a prognostic indicator at any dis- $ rst variceal hemorrhage (primary prophylaxis). Recommen- ease stage rather than a distinct stage of cirrhosis or as an event dations stated below follow recent treatment recommenda- de$ ning decompensation (1) . Nevertheless, the management of tions endorsed by the AASLD (American Association for the cirrhosis also involves the diagnosis and management of HCC. Study of Liver ) and the ACG (American College of A recent consensus conference established that compen- Gastroenterology) (5,6). sated cirrhosis should be considered a separate entity from Candidates for primary prophylaxis of variceal hemorrhage . decompensated cirrhosis with di@ erent management, progno- ! ree factors identify patients at a high risk of from sis, and causes of death (2) . ! erefore, the following treatment varices: large variceal size, red wale marks on the varices recommendations for cirrhosis are divided according to the (de$ ned as longitudinal dilated venules resembling whip marks status – compensated or decompensated – of the cirrhotic patient on the variceal surface), and advanced liver disease (CTP class with a separate section for the screening, diagnosis, and man- B or C) (8) . Patients with large varices or patients with high- agement of HCC, as this applies to both patients with compen- risk small varices (those with red signs or those occurring in a sated and decompensated cirrhosis. CTP class C patient) are at the highest risk of bleeding. Other ! e recommendations are based on evidence in the literature, patients with small varices (non-high risk) are at a low risk of mainly from randomized clinical trials (RCTs) and meta-analy- bleeding, but are at risk for variceal growth. ses of these trials. When few or no data exist from well-designed Accepted . Two therapies are currently accepted in the prospective trials, emphasis is given to results from large series prevention of the $ rst episode of variceal hemorrhage, namely and consensus conferences with involvement of recognized nonselective -blockers (NSBBs) and endoscopic variceal liga- experts. Clinical considerations may justify a course of action tion (EVL) (Supplementary Table 2 ) . that di@ ers from these recommendations. NSBBs (i.e., propranolol, nadolol) reduce portal pressure by Recommendations are summarized in the Cirrhosis and reducing the ( 1-blockade e@ ect) and, more HCC Quicknotes available at http://www.hepatitis.va.gov. importantly, by reducing portal blood inO ow through splanch- nic vasoconstriction ( 2-blockade e@ ect). ! erefore, selective  1-blockers (e.g., atenolol, metoprolol) are less e@ ective and are MANAGEMENT OF COMPENSATED CIRRHOSIS not recommended for the primary prophylaxis of variceal hem- Patients with compensated cirrhosis are not jaundiced and orrhage. Results from RCTs show that, in patients with varices, have not yet developed ascites, encephalopathy, or variceal NSBBs signi$ cantly reduce the incidence of $ rst variceal hem- hemorrhage. ! e median survival of patients with compen- orrhage, from 25 to 15 % in a median follow-up of 24 months sated cirrhosis is ~ 9 years (3), but it is as long as 12 years when (9) . ! e e@ ect is more evident in patients with medium / large- patients are censored at the time of decompensation (1) . sized varices (30 % $ rst hemorrhage in controls compared

© 2009 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY 1804 Garcia-Tsao et al.

with 14 % in NSBB-treated patients). Mortality is lower in the heart rates of 55 –60 b.p.m. Propranolol is administered twice a -blocker group compared with that in the control group, and day (b.i.d) and is usually started at a dose of 20 mg b.i.d. Nad- this di@ erence has been shown to be statistically signi$ cant olol is administered q.d. (once a day) and is started at a dose (10) . ! e incidence of $ rst variceal hemorrhage in patients with of 20 – 40 mg q.d. ! e NSBB on the Department of Veterans small varices, although low, is reduced with  - b l o c k e r s ( f r o m A@ airs (VA) National Formulary is propranolol (10, 20, 40, and 7 to 2 % over a period of 2 years); however, these numbers are 80 mg tablets). On the basis of data showing recurrent bleeding too small to show statistical signi$ cance. In patients with small on discontinuation of  -blockers (20) , it is recommended that

REVIEW REVIEW varices that are not at a high risk of hemorrhage, NSBBs have NSBBs be continued inde$ nitely. Importantly, once NSBBs are been e@ ective in delaying variceal growth, and thereby prevent- initiated and the dose is appropriately adjusted there is no need ing variceal hemorrhage (11) . for repeat EGD. EVL is a local therapy that consists of placing rubber bands EVL is performed every 1– 2 weeks until the obliteration of around varices until obliteration. EVL has been compared with varices, with $ rst surveillance EGD performed 1 – 3 months NSBB in several randomized trials in patients with large varices a% er obliteration and every 6 – 12 months therea% er. with or without red wale markings. Two meta-analyses show Contraindications/ side e ects . Approximately 15 % of patients that EVL is associated with a small but signi$ cantly lower inci- have contraindications to the use of NSBB, such as asthma, dence of $ rst variceal hemorrhage without di@ erences in mor- -dependent diabetes (with episodes of ), tality (12,13) . However, a more recent meta-analysis showed and peripheral . ! e most common side e@ ects that the estimated e@ ect of EVL in some trials may be biased related to NSBB in cirrhosis are lightheadedness, , and and was associated with the duration of follow-up (the shorter shortness of breath. Some of these side e@ ects disappear with the follow-up, the more positive the estimated e@ ect of EVL time or a% er a reduction in the dose of NSBB. In clinical tri- (14) ) and that both therapies seemed equally e@ ective. EVL is als, side e@ ects have led to treatment discontinuation in ~ 15 % cost-e@ ective when cost per quality-adjusted life year is consid- of patients. ! e rate of side e@ ects in trials in which nadolol ered (15) and is preferred over NSBB by both patients and phy- was used ( ~10 % ) seems to be lower than in trials in which pro- sicians (16) . However, NSBBs have other advantages, such as pranolol was used ( ~17 % ); however, direct comparisons have prevention of bleeding from other portal hypertension sources not been made (21). (portal hypertensive gastropathy and ) and a pos- Side e@ ects of EVL occur in ~ 14 % of cases and are usually sible reduction in the incidence of spontaneous bacterial peri- minor. ! e most common complications are transient dys- tonitis (SBP) (17) . phagia and chest discomfort. Shallow ulcers at the site of each A % er a careful review of the available data, a consen- ligation are the rule, and the use of proton pump inhibitors a% er sus panel concluded that both NSBB and EVL are e@ ective ligation seems to reduce their size (22) . However, there have in preventing $ rst variceal hemorrhage in patients with been reports of bleeding from ligation-induced esophageal medium/ large varices, and that the choice should be based ulcers that has resulted in death (23,24), and this risk should be on patient characteristics and on preferences, local resources, discussed with the patient. and expertise (2) .  erapies not recommended for primary prophylaxis . ! ese In patients with medium/ large-sized varices at the highest therapies are summarized in (Supplementary Table 2 ). Nitrates risk of bleeding (CTP class C, red wale marks) either NSBB (such as isosorbide mononitrate, ISMN) are ine@ ective in pre- or EVL can be used, whereas in patients with medium/ large venting $ rst variceal hemorrhage in patients with large varices varices that are not at the highest risk, NSBBs are preferred and (25,26) and have been associated with a higher mortality in EVL should be considered in patients with contraindications, patients older than 50 years (27) . ISMN, a potent venodilator, intolerance (including those in whom the dose of NSBB can- may lead to a higher mortality in these patients by aggravat- not be adjusted to achieve target goals), or non-compliance to ing the vasodilatory state of the cirrhotic patient, as shown in NSBB (5,6) . shorter-term hemodynamic trials using other vasodilators, In patients with small varices that are at a high risk of bleed- such as losartan (28) and irbesartan (29) . ! erefore, the use of ing (red wale marks and / or CTP class C), NSBBs are recom- nitrates alone in patients with cirrhosis should be discouraged, mended given the technical di culties in performing EVL. unless there is a clear indication for coronary artery disease. Patients with gastric fundal varices (with or without esopha- ! e combination of a NSBB and ISMN has a synergistic por- geal varices) should receive NSBB; prophylactic EVL is not tal pressure-reducing e@ ect and could theoretically be more recommended in these patients, given the risk of precipitating e@ ective than NSBB alone in preventing $ rst variceal hemor- hemorrhage. rhage (30) . Double-blind, placebo-controlled RCTs have shown In patients without varices, treatment is not recommended a lack of e cacy (31,32) and a greater number of side e@ ects given the lack of e cacy of NSBB in preventing the develop- with combination therapy (31) . ! erefore, the use of a combi- ment of varices and a higher rate of side e@ ects (18). nation of a -blocker and ISMN cannot be recommended for Treatment schedule. Given the lack of correlation between primary prophylaxis. decreases in heart rate and decreases in portal pressure (19), ! e combination of a NSBB and (which has the dose of NSBB is adjusted to the maximal tolerated doses to been shown to decrease portal pressure by reducing plasma

The American Journal of GASTROENTEROLOGY VOLUME 104 | JULY 2009 www.amjgastro.com Management and treatment of patients with cirrhosis and portal hypertension 1805

volume and splanchnic blood O ow) has not been shown to However, over-the-counter , speci$ cally acetami- increase the e cacy of nadolol in the primary prophylaxis of nophen (or ) and non-steroidal anti-inO ammatory variceal hemorrhage (33) . drugs (NSAIDs), including , ibuprofen, naproxen, and Endoscopic sclerotherapy trials yielded controversial results. sulindac, can potentially lead to decompensation in a patient Although early studies showed promising results, later studies with compensated cirrhosis or to further decompensation in showed no bene$ t in decreasing $ rst variceal hemorrhage or an already decompensated patient (“ acute-on-chronic ” liver mortality from variceal bleeding (34,35) . A VA prospective, f a i l u r e ) . randomized, cooperative trial that compared prophylactic scle- Acetaminophen is an intrinsic that produces REVIEW rotherapy with sham therapy was terminated 22.5 months a% er dose-related hepatocellular , with severe hepatotoxic- it began, because the mortality rate was signi$ cantly higher in ity resulting from a single acute ingestion of more than 15 g. the sclerotherapy group than in the sham-therapy group (36) . ! e at-risk dose is lower in individuals with chronic alcohol ! erefore, sclerotherapy should not be used for the primary use or malnutrition in whom therapeutic doses (4 g / day) can prevention of variceal hemorrhage. produce signi$ cant liver (41 – 43) . Patients with alcoholic ! e role of a combination of a NSBB and EVL in the pre- cirrhosis who are actively drinking and / or are malnourished vention of $ rst variceal hemorrhage is uncertain. In a rand- may be more susceptible to develop acute-on-chronic liver omized but not placebo-controlled trial that compared EVL injury from lower doses of acetaminophen (44) and therefore, alone with EVL + NSBB in patients with large varices and red in these patients acetaminophen should be used at doses lower signs, no di@ erences were observed in the incidence of bleed- than those recommended. In all other patients with cirrhosis, ing or death between groups (8 and 7% , respectively) (37) . In acetaminophen can be used at therapeutic doses but for lim- another RCT that compared NSBB alone with NSBB + EVL ited periods of time, as recent studies have shown that chronic in CTP class B or C patients with large varices and red signs, therapeutic use rather than acute massive ingestion of aceta- $ rst variceal bleeding was lower in patients treated with com- minophen is a more common of acute in the bination therapy (8 % ) compared with those treated with United States (45,46) . NSBB alone (30 %, a rate that is too high and comparable with NSAIDs, in addition to having a potential for idiosyncratic untreated patients) (38) . In both studies, side e@ ects were liver injury, inhibit prostaglandin synthesis and, by doing so, more common in EVL + NSBB groups. Given these conO ic- blunt the response to in patients with cirrhosis and tive results, combination therapy cannot be currently recom- ascites and promote renal vasoconstriction that will in turn lead mended. to decreased glomerular $ ltration rate and Shunt trials have shown conclusively that, although (AKI) (47,48) . Renal vasoconstriction and renal failure a% er very e@ ective in preventing $ rst variceal hemorrhage, shunt- NSAIDs occur not only in patients with decompensated cir- ing blood away from the liver is accompanied by more frequent rhosis, but also in those with compensated disease (49) . ! ere- encephalopathy and higher mortality (34) . ! ese results can fore, NSAIDs should be avoided in patients with cirrhosis. be extrapolated to the transjugular intrahepatic (TIPS), because its physiology is the same as that of sur- gical shunts (i.e., diversion of blood away from the liver) (39) . MANAGEMENT OF DECOMPENSATED CIRRHOSIS ! erefore, shunt therapy (surgery or TIPS) should not be used ! e following sections deal with the management of the spe- in the primary prevention of variceal hemorrhage. ci$ c complications of the patient with cirrhosis who has devel-  erapies under investigation . Recently, the preliminary oped decompensation. ! e $ rst two complications, acute results of a RCT comparing carvedilol (a NSBB with vasodi- variceal hemorrhage and SBP, are severe and require hospi- lating properties) with EVL in the primary prophylaxis of talization. HRS is also a severe complication of cirrhosis but variceal hemorrhage showed that a% er 16 months of follow-up, usually occurs in the patient who is already in the hospital. As carvedilol was associated with a signi$ cantly lower rate of $ rst HRS represents the result of extreme hemodynamic alterations variceal hemorrhage (9 %) compared with EVL (21 %) with a that lead to ascites formation, it is placed under treatment of tendency for higher rate of adverse events with carvedilol (40). ascites. ! e bleeding rate for EVL is higher than that reported earlier and, until details of this study are available, carvedilol cannot be Treatment of acute variceal hemorrhage recommended (Supplementary Table 2 ) . Acute variceal hemorrhage is associated with a mortality rate ! e management strategy a% er screening endoscopy in of 15– 20 % . Management should be aimed at providing simul- patients with newly diagnosed cirrhosis is summarized in taneous and coordinated attention to e@ ective , Table 1. prompt diagnosis, control of bleeding, and prevention of com- plications. Over-the-counter in compensated cirrhosis Candidates for therapy. Candidates include patients with Most drugs are metabolized in the liver and, although they are cirrhosis who present with upper gastrointestinal (GI) hemor- potentially hepatotoxic, the risk for hepatotoxicity is not nec- rhage and in whom diagnostic endoscopy shows one of the fol- essarily higher in patients with pre-existing liver disease. lowing: active bleeding from a varix, a “ white nipple” overlying

© 2009 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY 1806 Garcia-Tsao et al.

Table 1 . Management strategy after results of screening endoscopy in patients with cirrhosis

No varices Repeat endoscopy in 3 years (sooner if decompensation occurs)

Small varices In a CTP B / C patient or varices Nonselective  -blockers Start propranolol (20 mg b.i.d.) or with red signs (propranolol or nadolol) nadolol (20 mg q.d.) Titrate to maximal tolerable dose or a heart rate of 55 – 60 b.p.m.

REVIEW REVIEW No need to repeat EGD In a CTP A patient, without red Nonselective  -blockers optional Same as above signs If no  -blockers are given, repeat endoscopy in 2 years (sooner if decompensation occurs) Medium / large varices All patients independent of CTP Nonselective  -blockers Same as above class (propranolol, nadolol) or a Endoscopic variceal ligation Ligate every 1– 2 weeks until variceal obliteration First surveillance endoscopy 1– 3 months after obliteration, then every 6– 12 months indefi nitely

b.i.d., twice a day; b.p.m., beats/ min; CTP, Child – Turcotte – Pugh; EGD, esophagogastroduodenoscopy; q.d., once daily. a Choice depends on patient characteristics and preferences, local resources.

a varix, clots overlying a varix, or varices with no other poten- VIIa over standard therapy (59) . Although post hoc analysis tial source of bleeding (50) . of a sub-population of CTP classes B and C cirrhotic patients indicated that administration of recombinant factor VIIa sig- General measures . V o l u m e s h o u l d b e e x p a n d e d t o m a i n t a i n ni$ cantly decreased the proportion of patients with failure to a systolic blood pressure of 90 –100 mm Hg and a heart rate of control variceal bleeding, this was not con$ rmed in a subse- below 100 b.p.m. (4) . Colloids are more e@ ective than crystal- quent RCT (60) and therefore, recombinant factor VIIa is not loids and packed red blood cells in reaching optimal hemo- recommended (Supplementary Table 3 ) . dynamic and transport goals (51) . Transfusion goals Once the patient is hemodynamically stable, EGD should be are required to maintain a of ~ 8 g / dl (4) as, in performed. Although the Baveno consensus suggests a 12-h experimental studies, total blood restitution is associated with time frame for the performance of diagnostic endoscopy (4) , it increases in portal pressure (52) , and higher rates of rebleed- should be performed as soon as possible particularly in patients ing and mortality (53) . Endotracheal intubation should be per- with more severe bleeding. formed before EGD in patients with massive bleeding and a decreased consciousness level. Speci c measures to control acute hemorrhage and prevent One of the main complications associated with variceal hem- early recurrence . Accepted therapies . ! e most rational ap- orrhage is bacterial . Short-term prophy- proach in the control of acute variceal hemorrhage consists of laxis not only decreases the rate of bacterial but the combination of pharmacological and endoscopic therapy also decreases variceal rebleeding (54) and increases survival (Supplementary Table 3 ) . (55,56) . ! erefore, its use is considered a standard practice (57) . Pharmacological therapy has the advantages of being gener- Although oral norO oxacin at a dose of 400 mg b.i.d. for 7 days ally applicable and drugs with a low rate of adverse events, such was recommended by consensus (57) , a recent RCT suggests as somatostatin or analogs (, vapreotide), can be initi- that intravenous (i.v.) ce% riaxone (1 g / day) is more e@ ective in ated as soon as a diagnosis of variceal hemorrhage is suspected, patients with two or more of the following: malnutrition, ascites, before diagnostic EGD. Drugs used in this setting act by produc- encephalopathy, or serum >3 mg / dl (58) . However in ing splanchnic vasoconstriction and, thereby decreasing portal this study, most of the infections (six of seven) observed in the blood inO ow. RCTs comparing di@ erent pharmacological agents norO oxacin group were caused by quinolone-resistant - (vasopressin, somatostatin, terlipressin, octreotide, vapreotide), isms suggesting that, norO oxacin would still be optimal in cent- show no di@ erences among them regarding control of hemor- ers with a low prevalence of quinolone resistance. rhage and early rebleeding, although vasopressin is associated ! e transfusion of fresh frozen plasma and can be with more adverse events (9) . In practice, the choice of phar- considered in patients with signi$ cant and / or macological agent is usually based on availability and cost. Of . A multicenter placebo-controlled trial of the safe vasoconstrictors (somatostatin and analogs, terlipres- recombinant factor VIIa in cirrhotic patients with GI hemor- sin), octreotide is currently the only one available in the United rhage failed to show a bene$ cial e@ ect of recombinant factor States and on the Department of VA National Formulary.

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Regarding endoscopic therapy, EVL is more e@ ective than for , the Linton tube, with a larger gastric endoscopic variceal sclerotherapy with greater control of hem- balloon (and no esophageal balloon) is preferred for uncon- orrhage, less rebleeding, lower rates of adverse events, but with- trolled bleeding from fundal gastric varices. ! e use of self- out di@ erences in mortality (13,61) . EVL should be performed expandable transient metallic stents to arrest uncontrollable at the time of diagnostic EGD if and when a variceal source of acute variceal bleeding has been reported in a pilot study of hemorrhage is con$ rmed. Sclerotherapy is reserved for cases in 20 patients to be associated with bleeding cessation in all which EVL cannot be performed. patients, and without complications a% er its removal 2– 14

Treatment schedule . Octreotide is recommended at an initial days later (69) . REVIEW bolus dose of 50 μ g i.v. followed by a continuous i.v. infusion Compared with endoscopic variceal sclerotherapy or EVL, of 50 μ g / h. Although the optimal duration of pharmacologi- endoscopic variceal obturation with adhesives, such as cal therapy has not been well established in RCTs, consider- N -butyl-cyanoacrylate is more e@ ective in treating acute fundal ing that ~ 50 % of early recurrent hemorrhage occurs within the gastric variceal bleeding, with better control of initial hemor- $ rst 5 days (62) , continuing vasoactive drugs for 5 days seems rhage, as well as lower rates of rebleeding (70,71) . A relatively rational. However, as shorter lengths of treatment have also large prospective RCT compared endoscopic variceal obtura- been successful, shorter duration is acceptable, particularly in tion using N -butyl-cyanoacrylate with EVL in patients with patients with a low risk of rebleeding (e.g., CTP class A). acute gastric variceal hemorrhage and showed that control of EVL should be performed during diagnostic endoscopy when active bleeding was similar in both groups, but that rebleeding the possible variceal source of bleeding is con$ rmed. ! e proc- over a follow-up period of 1.6 – 1.8 years occurred signi$ cantly ess should be started at the gastroesophageal junction by placing less frequently in the endoscopic variceal obturation group ~ 6 bands particularly on the vessel with stigmata of bleeding. (23 vs. 47 % ), with an average of only 1.5 sessions (range 1 – 3) Repeat EVL can be attempted if hemorrhage is not controlled or (72) . In an uncontrolled pilot study, 2-octyl cyanoacrylate, an if the patient has an early recurrence of variceal hemorrhage. agent approved for skin closure in the United States, has been Side e ects . Octreotide (and other somatostatin analogs) are described to be e@ ective in achieving initial hemostasis and in safe and can be used continuously for many days (5 days in most preventing rebleeding from fundal varices (73) . trials). Complications of EVL in the acute setting are similar to  erapies under investigation. TIPS is currently considered to those described above in the primary prophylaxis of variceal be a salvage therapy in the control of acute hemorrhage. How- hemorrhage. ever, a small randomized controlled trial of 116 consecutive Other therapies. Despite an urgent endoscopic and/ or phar- cirrhotic patients with acute variceal bleeding who received a macological therapy, variceal bleeding cannot be controlled or single session of sclerotherapy injection during urgent endos- recurs early in approximately 10 – 20 % of patients, and other copy, suggested that early TIPS placement (within 24 h of hem- therapies should be implemented. An increased portal pres- orrhage) was associated with signi$ cantly improved survival in sure, as measured by the hepatic venous pressure gradient high-risk patients (i.e., those with an HVPG >20 mm Hg) and (HVPG) within 24 h of presentation, predicts treatment failure may play an earlier role in treatment of acute variceal hemor- (63,64) . rhage (74) . Recently, the preliminary results of a multicenter Shunt therapy, either shunt surgery (in CTP class A patients) RCT of early covered TIPS (performed within 72 h) in patients or TIPS, has proven clinical e cacy as salvage therapy for with CTP class B and active hemorrhage at endoscopy or in patients who fail to respond to endoscopic or pharmacological patients with CTP class C, showed a signi$ cant survival ben- therapy (65,66) . A surgical group has reported an almost uni- e$ t in patients randomized to TIPS compared with those who versal control of bleeding and low mortality with the perform- received standard therapy (75) . ! erefore, it would seem that, in ance of portocaval shunt within 8 h a% er the onset of bleeding high-risk patients, early TIPS is a reasonable alternative; how- in unselected cirrhotic patients collected over a 30-year period ever, this cannot be recommended until more data are available (67) . ! is approach has not been validated by other groups and (Supplementary Table 3 ) . is not widely practiced. ! e strategy in the diagnosis and management of patients Balloon tamponade is very e@ ective in controlling bleed- with acute variceal hemorrhage is summarized in Table 2. ing temporarily with immediate control of hemorrhage in > 80% of patients (68) . However, rebleeding a% er the bal- Prevention of recurrent variceal hemorrhage . P a t i e n t s w h o loons are deO ated is high and its use is associated with poten- survive an episode of acute variceal hemorrhage have a very tially lethal complications, such as aspiration, migration, and high risk of rebleeding and death. ! e median rebleeding rate necrosis / perforation of the with mortality rates as in untreated individuals is ~ 60 % within 1 –2 years of the index high as 20% . ! erefore, it should be restricted to patients with hemorrhage, with a mortality rate of 33 % (9) . ! erefore, it is uncontrollable bleeding for whom a more de$ nitive therapy essential that patients who survive an episode of variceal hem- (e.g., TIPS) is planned within 24 h of placement. Airway pro- orrhage be started on therapy to reduce the risk of hemorrhage tection is strongly recommended when balloon tamponade recurrence, before discharge from the hospital. Patients who is used. Although the Sengstaken – Blakemore tube (with required shunt surgery/ TIPS to control the acute episode do both an esophageal and a gastric balloon) is recommended not require further preventive measures.

© 2009 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY 1808 Garcia-Tsao et al.

with 47 and 38 % , respectively for the EVL arm alone. ! ese Table 2 . Diagnosis and management strategy of patient with results support the use of the combination of EVL + NSBB in acute variceal hemorrhage preventing rebleeding (5,6) . ! e c o m b i n a t i o n E V L + N S B B i s Diagnosis Any of the following fi ndings on upper clearly recommended in patients who develop variceal hem- endoscopy performed within 12 h of orrhage ($ rst or recurrent) while on EVL or a NSBB alone admission: (Supplementary Table 4 ) . Active bleeding from a varix or Stigmata of variceal hemorrhage ! e lowest rate of variceal rebleeding (~ 10 % ) occurs in

REVIEW REVIEW (white nipple sign) or patients for whom portal pressure (assessed by HVPG) Presence of gastroesophageal varices decreases signi$ cantly; i.e., in patients for whom pharmaco- without another source of hemorrhage logical therapy (either a NSBB alone or NSBB plus nitrates) General management Cautious transfusion of fl uids and leads to a reduction in HVPG to < 12 mm Hg or a reduction blood products, aiming to maintain a of >20% from baseline (79,80) . As suggested recently, perhaps hemoglobin of ~ 8 g / dl the most rational therapy would be to adapt the di@ erent thera- Antibiotic prophylaxis (3– 7 days) with: pies for preventing variceal rebleeding in the context of HVPG Ciprofl oxacin 500 mg b.i.d. (p.o.) or 400 mg b.i.d. (i.v.) or response (81,82) ; however, this would require standardization of the HVPG technique, including the best timing to perform Ceftriaxone 1 g / day (i.v.) particularly in facilities with known quinolone resistance the repeat HVPG measurement (2) and con$ rmation of studies and in patients with two or more of the that suggest that the acute response to i.v. propranolol predicts following : malnutrition, ascites, encepha- the recurrence of variceal hemorrhage (83,84) . lopathy, serum bilirubin > 3 mg / dl Treatment schedule . ! e treatment schedules for NSBB (i.e., Specifi c initial management Pharmacological therapy initiated as propranolol, nadolol) and for EVL are the same as described soon as diagnosis is suspected above (see “ Screening for gastroesophageal varices and primary Octreotide 50 mcg i.v. bolus followed prophylaxis of variceal hemorrhage ” ) in the prevention of $ rst by continuous infusion 50 mcg / h (3 – 5 days) and variceal hemorrhage. Side e ects . ! e side e@ ects of a combination of pharmaco- Endoscopic therapy (ligation prefer- able) performed at time of diagnostic logical plus endoscopic therapy are those of each therapy sepa- endoscopy (performed within 12 h of rately. However, given the greater risk of recurrent hemorrhage admission) in 1 – 2 years compared with the risk of $ rst hemorrhage (60 Rescue management Considered in patients with bleeding vs. 20 %, respectively), a more aggressive therapy with a greater esophageal varices who have failed number of side e@ ects is justi$ able in the secondary prophy-

pharmacological + endoscopic therapy laxis of variceal hemorrhage. or in patients with bleeding gastric fundal varices who have failed one Alternative therapies . ! e combination of a NSBB and ISMN endoscopic therapy: has a synergistic portal pressure-reducing e@ ect and could the- TIPS or oretically be more e@ ective than NSBB alone. Only one study Shunt therapy (CTP A patients where has performed a direct comparison between the combination of available) propranolol plus ISMN and propranolol alone (85) . ! is study b.i.d., twice a day, CTP, Child – Turcotte – Pugh; i.v., intravenous; p.o., orally; showed a bene$ t of combination therapy (33 % vs. 41 % rebleed- TIPS, transjugular intrahepatic portosystemic shunt. ing rate), but it was not statistically signi$ cant. Data collected from di@ erent RCTs showed lower median rebleeding rates (~ 33 % ) in patients treated with combined pharmacological Candidates . Candidates are patients who have recovered from therapy compared with rebleeding rates in patients treated with an episode of acute variceal hemorrhage, have had no evidence NSBB alone ( ~ 50 % ) (9) . However, a recent RCT showed that of hemorrhage for at least 24 h, and in whom pharmacological variceal rebleeding in a group treated with NSBB + ISMN + EVL therapy for the control of acute variceal hemorrhage has been (18% ) was signi$ cantly lower than in a group treated with or is being discontinued. NSBB + ISMN without EVL (32% ) (86), but with rates similar to Accepted therapies. A combination of EVL plus pharmaco- those described for combination NSBB + EVL (14 % and 23% ). logical therapy is the most rational approach, because NSBBs Side e@ ects are more frequent with the combination therapy will protect against rebleeding before variceal obliteration and (NSBB plus nitrates) than with NSBB alone, mostly in terms will delay variceal recurrence. A recent meta-analysis showed of and weakness (9), and have led to a higher rate of that a combination of endoscopic (sclerotherapy or EVL) and treatment discontinuation than with NSBB alone (85) . It would drug therapy reduces overall and variceal rebleeding in cirrho- seem reasonable that, if a patient is not a candidate for EVL, sis more than either therapy alone (76) . Two randomized tri- one would try to maximize portal pressure reduction by giving als show the superiority of EVL + NSBB vs. EVL alone (77,78) . combination pharmacological therapy. Rebleeding rates in these 2 trials were 23 and 14 % , respectively, Shunt surgery is very e@ ective in preventing rebleeding; how- for EVL plus nadolol, which was signi$ cantly lower compared ever, it markedly increases the risk of HE, without any e@ ect

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on survival (34,87) . Not surprisingly, recent meta-analyses of Treatment of SBP 11 trials that compared TIPS with endoscopic therapy showed ! e most common infections in cirrhosis are the so-called similar results (88,89) . ! at is, even though rebleeding is signi$ - “ spontaneous ” infections, namely SBP, spontaneous bacterial cantly less frequent with TIPS, post-treatment encephalopathy empyema, and spontaneous bacteremia, which share patho- occurs signi$ cantly more o% en a% er TIPS, without di@ erences in genic mechanisms and management. ! ey are called spontane- mortality. Furthermore, a recent trial showed that, even though ous because there is no obvious source of that would TIPS was more e@ ective than pharmacological (propranolol explain their spread to ascites, pleural O uid or blood. plus nitrates) therapy in preventing rebleeding, it was associated SBP occurs in 10 –20 % of hospitalized patients with cirrhosis REVIEW with more encephalopathy, identical survival, and higher costs and ascites, mainly in those with severe liver disease. When $ rst (90) . ! erefore, TIPS should not be used as a $ rst-line treat- described, its mortality rate exceeded 80 % ; however, with early ment, but rather as a rescue therapy for patients who have failed recognition of the disease and prompt and appropriate antibiotic to respond to pharmacological plus endoscopic treatment. therapy, in-hospital mortality from an episode of SBP has been  erapies not recommended for secondary prophylaxis . reduced to approximately 10 – 20 % (95) . Early diagnosis is a key ! ese therapies are summarized in (Supplementary Table 4 ) . issue in the management of SBP. It is recommended that a diag- Although NSBB alone and sclerotherapy reduce variceal nostic should be performed in any patient (i) admit- rebleeding and death rates in treated controls compared with ted to the hospital with cirrhosis and ascites; (ii) with cirrhosis and untreated controls, rebleeding rates of 42– 43 % with these ther- ascites who develops compatible symptoms or signs (abdominal apies are still unacceptably high in treated patients (9,34,91) pain or tenderness on palpation, , or chills); and (iii) with cir- and therefore, these therapies are no longer recommended. ! e rhosis and ascites and with worsening renal or liver function (57) . pharmacological therapy of choice in the prevention of variceal ! e diagnosis is established with an ascites PMN (polymor- rebleeding is the combination of a NSBB and a nitrate. phonuclear) cell count of > 250 / mm 3. It has been suggested that Even though EVL alone is clearly superior to sclerotherapy a faster, inexpensive method for diagnosing SBP is through the (91,92) and equivalent to a combination of  - b l o c k e r s p l u s use of reagent strips similar to those used in the rapid diagnosis of nitrates (93) , the combination of EVL plus pharmacological ther- urinary tract infections; however, this practice cannot be recom- apy is superior to EVL alone and, as mentioned above, should be mended as a recent review showed a false negative rate ranging preferred in the secondary prophylaxis of variceal hemorrhage. between 0 and 50% (96). Moreover, in the largest series of patients Trials suggest that EVL is followed by a higher rate of variceal with SBP, using the Multistix 8 SG (Bayer Pharma SAS, Puteaux, recurrence in comparison with sclerotherapy. Even though France), the false negative rate was unacceptably high at 55 % (97) . meta-analysis shows no signi$ cant di@ erence in variceal recur- If a traumatic or bloody tap is suspected (i.e., ascitic red blood cells rence between treatments (91) , the e cacy of the combination > 10,000), care should be taken to subtract 1 PMN for every 250 of EVL plus sclerotherapy compared with EVL alone in reduc- red blood cells. Separate and simultaneous blood cultures should ing variceal recurrence has been explored. A recent meta-anal- be collected, as 50% of all SBP cases are associated with bacteremia. ysis of seven such trials showed that the combination of EVL In patients with hepatic hydrothorax in whom an infection is sus- and sclerotherapy o@ ers no advantage over EVL alone regard- pected and in whom SBP has been ruled out, a diagnostic thora- ing the prevention of rebleeding or reduction of mortality and centesis should be performed as spontaneous bacterial empyema is associated with a higher complication rate (94) . ! erefore, may occur in the absence of ascites or SBP (98). To increase the the evidence accumulated so far should discourage the use of sensitivity of the bacteriological culture, ascites and /or pleural the combination of EVL plus sclerotherapy. O uid should be inoculated at the patient ’ s bedside into blood cul- ! e strategy in the prevention of recurrent variceal hemor- ture bottles (57,99) . Even with these careful measures, 30 – 50 % of rhage is summarized in Table 3. the time, the causative organism is not isolated (57,100) .

Table 3 . Management strategy in the prevention of recurrent variceal hemorrhage (secondary prophylaxis)

First-line therapy Nonselective β -blockers (propranolol, nadolol) Start propranolol (20 mg b.i.d.) or nadolol (20 mg q.d.) Titrate to maximum tolerable dosage or a heart rate of 55 – 60 b.p.m. No need for repeat endoscopy and Endoscopic variceal ligation Ligate every 1 – 2 weeks until variceal obliteration First surveillance endoscopy 1– 3 months after obliteration, then every 6– 12 months Second-line therapy (if combined pharmaco- TIPS or logic +endoscopic treatment has failed) Shunt surgery (CTP class A patients, where available)

b.i.d., twice a day; b.p.m., beats/ min; CTP, Child– Turcotte – Pugh; TIPS, transjugular intrahepatic portosystemic shunt; q.d., once daily.

© 2009 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY 1810 Garcia-Tsao et al.

! e following management for spontaneous infections is Dose and duration . ! e dose of cefotaxime used in clinical based on evidence in the literature and results of a consensus trials ranges between 2 g i.v. every 4 h and 2 g i.v. every 12 h. conference on the diagnosis and management of SBP spon- One randomized study compared two di@ erent dose sched- sored by the International Ascites Club (57) . ules of cefotaxime (2 g every 6 h vs. 2 g every 12 h) and showed similar rates of SBP resolution and patient survival with both Treatment of the acute infection . ! erapies are summarized schedules (103) . ! erefore, the recommended dose of cefotax- in Supplementary Table 5 . Accepted therapies. Once a diag- ime is 2 g i.v. every 12 h. Ce% riaxone has been used at a dose of

REVIEW REVIEW nosis of SBP is established, antibiotic therapy should be initi- 1 – 2 g i.v. every 24 h and ce% azidime at a dose of 1 g i.v. every ated, before obtaining the results of ascites or blood cultures. 12 – 24 h. ! e only study assessing the combination of amoxicil- ! e antibiotic that has been most widely used is i.v. cefotax- lin– used a dose of 1 –0.2 g i.v. every 8 h (108) . ime, which leads to SBP resolution in ~90 % of the patients A control paracentesis performed 48 h a% er starting therapy (101 – 103); although in recent studies, cefotaxime has been is recommended to assess the response to therapy (57) . If a successful in only 60 – 70 % of the episodes (104) , with a suc- clinical improvement is obvious, this control paracentesis may cess rate as low as 44 % in nosocomial SBP (105) because of not be necessary. If the PMN count has not decreased by at the presence of multi-drug-resistant organisms. Other third- least 25 % from baseline, antibiotic coverage should be broad- generation , such as ce% riaxone, have been ened and investigations to rule out secondary peritonitis may shown to be as e@ ective as cefotaxime in uncontrolled studies be initiated depending on the isolated (if any) (106,107) . In a RCT, the combination of i.v. and and clinical status. clavulanic acid was shown to be as e@ ective and safe as i.v. Antibiotic treatment can be safely discontinued a% er the cefotaxime in the treatment of SBP (108); however as for cefo- ascites PMN count decreases to below 250 /mm 3 , which occurs taxime, lower e cacy and a high rate of antibiotic resistance in a mean period of 5 days (116) . In a comparative study, a 5- has been shown recently (109) , particularly in nosocomial day therapy with cefotaxime was as e@ ective as a 10-day therapy infections (105) . Patients who develop SBP on prophylactic (102) and therefore, it has been recommended that antibiotic quinolones respond as well to cefotaxime as patients not on therapy should be maintained for a minimum of 5 days (57) . prophylaxis (110) . However, given that the median time to SBP resolution in con- Cefotaxime is on the VA National Formulary but may be trolled trials is 8 days, this latter duration of 8 days is probably restricted at the facility or VISN (Veterans Integrated Serv- preferable (117) . It is reasonable to consider switching to an ice Network) level. However, other third-generation cepha- oral antibiotic a% er 48 h of therapy in patients who show clini- losporins, such as ce% riaxone, are available and should be equally cal improvement (108,118,119), as this will allow for an early e@ ective. ! e i.v. preparation of amoxicillin and clavulanic acid discharge with lower costs (119) . is unavailable in the United States but another  - l a c t a m / - ! e dose of i.v. albumin as adjuvant to antibiotic therapy that lactamase combination, such as ampicillin/ sulbactam, would has been used is arbitrary: 1.5 g / kg of body weight during the have a similar spectrum of activity. ! e susceptibility patterns $ rst 6 h, followed by 1 g / kg on day 3 (111), although it would of individual practice settings should be taken into considera- seem rational to tailor the dose to improvement (or lack of tion when selecting the antibiotic for SBP. improvement) in serum . Intravenous albumin has been shown to be an important Side e ects . ! e recommended above have been adjuvant to antibiotic therapy in patients with SBP. A RCT com- associated with very few side e@ ects and no renal toxicity. paring cefotaxime plus albumin with cefotaxime alone showed Cirrhotic patients have an increased propensity for develop- that patients who received albumin had signi$ cantly lower ing aminoglycoside-induced nephrotoxicity and therefore, rates of renal dysfunction (10 vs. 3 %), in-hospital mortality aminoglycosides should be considered as a last resort in the rate (10 vs. 29 % ), and a 3-month mortality (22 vs. 41 % ) (111) . therapy of infections in cirrhotic patients (120) . ! e rationale behind albumin administration is to improve the Alternative therapies. In patients with community-acquired, decreased e@ ective arterial blood volume that results from SBP uncomplicated SBP (i.e., no renal dysfunction or encepha- and that leads to renal dysfunction, which is the main cause of lopathy), an RCT showed that oral oO oxacin, a fully absorbed death in patients with SBP, although albumin may also act by quinolone, is a good alternative (121) . Although theoretically binding endotoxin and reducing and nitric oxide lev- other widely biovailable quinolones, such as ciproO oxacin and els (112) . Albumin should be administered to patients at a high levoO oxacin, could be used orally, they have not been investi- risk of developing renal dysfunction, i.e., those with a serum gated in clinical trials and the rising prevalence of quinolone- bilirubin >4 mg / dl and evidence of renal impairment at base- resistant organisms limits their applicability. line (blood >30 mg / dl and / or creatinine >1.0 mg / ! e use of extended spectrum antibiotics (e.g., , dl) (111,113,114) . In fact, a recent study showed that patients / ) as initial empirical therapy should be with “ low-risk ” SBP (i.e., those with serum creatinine < 1 mg / dl considered in patients with nosocomial SBP (105) . and urea < 30 mg / dl), who represent approximately half of the  erapies that should not be used . As mentioned above, patients with SBP, have a good outcome that does not improve aminoglycosides should be avoided in cirrhosis (120) . As large with i.v. albumin administration (115) . volume paracentesis (LVP) can be associated with vasodilata-

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Table 4 . Diagnosis and management strategy in spontaneous bacterial peritonitis (SBP)

Diagnosis Consider SBP and perform diagnostic paracentesis if: Symptoms / signs (, fever, chills) Patient is in emergency room or admitted Worsening renal function or encephalopathy SBP present if ascites PMN count > 250 cells/  l (if fl uid bloody, subtract 1 PMN per 250 RBC/  l)

General management Avoid therapeutic paracenteses during active infection REVIEW REVIEW Intravenous albumin (1 g / kg of body weight) if BUN > 30 mg / dl, creatinine > 1 mg / dl, bilirubin > 4 mg / dl; repeat at day 3 if renal dysfunction persists Avoid aminoglycosides Specifi c management Cefotaxime (2 g i.v. every 12 h) or Ceftriaxone (2 g every 24 h) or Ampicillin / sulbactam (2g/ 1 g i.v. every 6 h) Follow-up Continue therapy for 7 days Repeat diagnostic paracentesis at day 2 If ascites PMN count decreases by at least 25% at day 2, can be switched to oral therapy (quinolone such as ciprofl oxacin or levofl oxacin 250 mg p.o. b.i.d.) to complete 7 days of therapy

b.i.d., twice a day; BUN, ; i.v., intravenous; PMN, polymorphonuclear () cell count; p.o., orally; RBC, red blood cell count.

tion (122) and theoretically can contribute to precipitating renal Contraindications/ side e ects . ! e development of infec- dysfunction in patients with SBP (who are already predisposed tions by quinolone-resistant organisms is the main complica- because of the presence of a bacterial infection), the perform- tion of long-term norO oxacin prophylaxis. In a study carried ance of LVP should be delayed until a% er the resolution of SBP. out in a large number of cirrhotic patients hospitalized with Similarly, medications that can potentially decrease e@ ective an infection, gram-negative bacteria isolated from patients on intravascular volume, such as diuretics, should be avoided dur- long-term quinolone prophylaxis were signi$ cantly more likely ing acute infection. to be not only quinolone-resistant but also / ! e strategy in the diagnosis and management of SBP is -resistant compared with those of patients summarized in Table 4. not on prophylaxis (100) . Alternative therapies . N o r O oxacin is not on the VA National Prevention of recurrent SBP . In p a t i e n t s w h o s u r v i v e a n e p i -Formulary; however, other quinolones with a similar spectrum, sode of SBP, the 1-year cumulative recurrence rate is high, at such as ciproO oxacin or levoO oxacin, could theoretically be ~ 70 % . ! erefore, it is essential that patients who have recovered used instead; the latter with the added advantage of gram-posi- from an episode of SBP be started on antibiotic prophylaxis to tive coverage. prevent recurrence before they are discharged from the hospi- Although a study has described that ciproO oxacin admin- tal. ! erapies are summarized in Supplementary Table 6. istered weekly (750 mg / week) can prevent SBP (126) , it had Accepted therapies. In a double-blind, placebo-controlled methodological problems and, additionally, the use of inter- study, continuous oral was shown to signifi- mittent ciproO oxacin has been related to a higher occur- cantly decrease the 1-year probability of developing recur- rence of quinolone-resistant organisms in stool specimens rent SBP from 68 % (in the placebo group) to 20 % (in the (127) . In a more recent RCT, daily norO oxacin (400 mg / day) norfloxacin group) (123) . The reduction in SBP caused by was more e@ ective than weekly ruO oxacin (400 mg / week) in gram-negative organisms was even more dramatic, from preventing recurrent SBP due to Enterobacteriaceae (125) . 60% to 3% . Prophylactic therapy was discontinued after ! erefore, quinolones administered weekly cannot be recom- 6 months of therapy and therefore, the effect on survival mended (Supplementary Table 6 ). Another trial using oral was not evaluable. As the median survival of patients who trimethoprim/ sulfamethoxazole (one double-strength tablet develop SBP is ~ 9 months (124) , antibiotic prophylaxis in daily, 5 days per week) (128) also showed e cacy in preventing this setting does not imply an inordinately prolonged period SBP. However, this trial included patients with an earlier history of administration. of SBP and those who had never experienced an episode of SBP, Dose and duration . ! e dose of norO oxacin used in studies hindering the interpretation of these results. Nevertheless, in of secondary prophylaxis of SBP is 400 mg by mouth (po) q.d. patients who are unable to take quinolones, this alternative is (123,125) . Prophylaxis should be continued until liver trans- reasonable. plantation or until the disappearance of ascites (likely to occur ! e strategy in the prevention of recurrent SBP is summa- in alcoholics who stop alcohol ingestion). rized in Table 5.

© 2009 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY 1812 Garcia-Tsao et al.

decrease in renal function (135) and therefore, cyclooxygenase- Table 5. Management strategy in the prevention of recurrent SBP 2 inhibitor use should also be avoided until more clinical data Recommended therapy Oral norfl oxacin 400 mg p.o. q.d. become available. (preferred) or Long-term antibiotic prophylaxis in the prevention of the $ rst Oral ciprofl oxacin 250– 500 mg episode of SBP (i.e., primary prophylaxis) in patients with cir- q.d. a or rhosis and ascites is controversial. Given the risk of developing Oral levofl oxacin 250 mg q.d. a antibiotic-resistant organisms (100,136) , the long-term use of

REVIEW REVIEW prophylactic antibiotics should be restricted to the sub-popula- Alternative therapy TMP-SMX 1 double-strength tablet p.o. q.d. tion of patients at the highest risk of developing SBP. Low ( < 1 – (Patients who develop quinolone- 1.5 g / dl) total levels in ascites are useful for determining resistant organisms may also the susceptibility of developing SBP (137) ; however, the prob- have resistance to TMP-SMX) ability of developing SBP in unselected patients with low ascites Duration Prophylaxis should be continued protein level is still low (9 –14 % ) in control groups of prospec- until the disappearance of ascites tive RCTs (138,139) and does not justify prophylaxis in all of or until liver transplantation them. In a recent placebo-controlled study that selected patients p.o., orally; SBP, spontaneous bacterial peritonitis; TMP-SMX, trimethoprim- with low ( < 1.5 g / l) ascites protein who also had advanced liver sulfamethoxazole; q.d., once daily. a Empirical doses. failure (CTP score ≥ 9 and serum bilirubin ≥ 3 mg / dl) or renal dysfunction (serum creatinine ≥ 1.2 mg / dl, blood urea nitrogen level ≥ 25 mg / dl, or serum sodium level ≤ 130 mEq / l) norO oxacin Treatment of ascites at a dose of 400 mg p.o. q.d. was associated with a reduction in Ascites is one of the most frequent complications of cirrhosis. the 1-year probability of SBP (7 vs. 61 % ), HRS (28 vs. 41 % ), and In compensated cirrhotic patients, ascites develops at a 5-year 3-month mortality rate (140) . It must be noted that all patients cumulative rate of ~ 30 % (3) . Once ascites develops, the 1-year included in the study were initially hospitalized, less than half of survival rate is ~ 50 % compared with the 1-year survival rate the patients with low ascites protein met entry criteria, and the of >90 % in patients with compensated cirrhosis (3,129 – 131) . survival bene$ t did not extend to 1 year. However, it is in this is particularly poor in patients who develop refrac- selected sub-population of patients with cirrhosis and ascites, tory ascites (132) or HRS (133) . that prophylaxis with norO oxacin (400 mg po q.d.) should be Treatment of ascites has not resulted in signi$ cant improve- undertaken. Another placebo-controlled study that targeted ments in survival. However, treating ascites is important, not patients with low ascites protein and low risk of developing only because it improves the quality of life of the cirrhotic SBP (serum bilirubin < 3.2, platelet count < 98,000) showed patient but also because SBP, a lethal complication of cir- a tendency for lower SBP rate (4 vs. 14 %, P = 0.16) and lower rhosis, does not occur in the absence of ascites. Patients go mortality (12 vs. 28 % , P = 0.08) in patients treated with oral cip- through a sequence of -responsive ascites, followed roO oxacin compared with placebo (139); however, the study is by refractory ascites, and then HRS. underpowered and no $ rm conclusions can be drawn from it.

General measures . C o n t r a r y t o t h e t r e a t m e n t o f h e a r t f a i l u r e , Management of uncomplicated ascites . Candidates . Candi- in which achieving a negative sodium and water balance im- dates are cirrhotic patients with ascites not associated with plies a certain urgency given the risk / presence of pulmonary infection or renal dysfunction (141) . Recommendations for edema, cirrhotic ascites therapy is not an emergency as the uncomplicated cirrhotic ascites apply to patients with uncom- risk of death is not implicit unless the O uid becomes infected. plicated hepatic hydrothorax (Supplementary Table 7 ). Diu- ! erefore, treatment of patients with cirrhosis and ascites is retics can lead to a reduction in intravascular volume and to based on oral (not i.v.) diuretics in a stepwise slow manner renal dysfunction and should not be initiated in patients with and should only be initiated in a “ stable ” cirrhotic patient, i.e., rising creatinine. In addition, diuretics should not be initiated in a patient for whom complications, such as GI hemorrhage, in patients with concomitant complications of cirrhosis known bacterial infection, and renal dysfunction are absent or have to be associated with decreased e@ ective arterial blood volume, resolved. In a patient with tense ascites who experiences ab- such as variceal hemorrhage or SBP. dominal discomfort and/ or respiratory distress, a single LVP Accepted therapies . Sodium restriction is recommended for can be performed before or concomitant to starting diuretic all cirrhotic patients with ascites. Although dietary sodium therapy. should be restricted to levels lower than urinary sodium As mentioned above, NSAIDs, including aspirin, blunt the excretion, sodium restriction to 88 mEq / day (i.e., 2 g of sodium natriuretic e@ ect of diuretics and should be avoided in cirrhotic per day or 5.2 g of dietary salt per day, considering that 1 mEq patients with ascites (47,48) . Although selective cyclooxygen- of sodium = 23 mg of sodium = 58.5 mg of dietary salt) is a real- ase-2 inhibitors have not been shown to impair natriuresis or istic goal, particularly in an outpatient setting. Patients with a to induce renal dysfunction in cirrhotic rats (134) , preliminary baseline urinary sodium excretion >50 mEq / day may respond data in patients indicate that celecoxib may be related to a to salt restriction alone. Most patients will require the addition

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of diuretics. Clinicians should be cautious about the nutritional Side e ects . Common complications of diuretic therapy status of patients on sodium restriction, as the non-palatability include renal impairment due to intravascular volume deple- of a salt-restricted diet may lead to an inadequate food intake. tion (25% ), (28% ), and HE (26% ) (145,146,148) . In these cases, liberalizing sodium restriction and adding diu- Development of these side e@ ects warrants diuretic dose reduc- retics is preferable to further impairment of the already com- tion or discontinuation. Spironolactone is o% en associated with promised nutrition of the cirrhotic patient with ascites. adverse events related to its anti-androgenic activity, mainly Spironolactone is the diuretic of choice. Even though loop painful gynecomastia. diuretics, such as furosemide, are more potent natriuretic Alternative therapies . canrenoate, one of the major REVIEW agents, randomized controlled trials have shown that spironol- metabolites of spironolactone, has a comparable diuretic e@ ect actone is signi$ cantly more e@ ective than furosemide alone in and a lower anti-androgenic activity and could be used in the treatment of cirrhotic ascites (142,143) . Diuretic therapy can cases in which gynecomastia and mastalgia are side e@ ects of be initiated with spironolactone alone or with spironolactone spironolactone therapy. However, this drug is not available in plus furosemide. Both therapies are equally e@ ective and can be the United States. Amiloride, another potassium-sparing diu- used; however, dose adjustments are needed more frequently retic, does not produce gynecomastia and is recommended in patients for whom treatment is initiated using combination in patients with intolerable painful gynecomastia, but it has a therapy because of more rapid increases in blood urea nitro- signi$ cantly lower natriuretic e@ ect than spironolactone (149) . gen and / or decreases in serum sodium (142,144) . ! erefore, it Amiloride is used at an initial dose of 20 mg / day and can be is preferable to initiate therapy with spironolactone alone. In increased to 60 mg / day. For patients whose natriuretic response patients who develop renal dysfunction (elevation in creatinine on amiloride is suboptimal, it may be worthwhile to attempt a >50% to creatinine >1.5 g / dl), diuretics should be temporar- retreatment with spironolactone. ily discontinued and restarted at a lower dose a% er creatinine Therapies that should not be used . Furosemide alone returns to baseline. Patients who develop hyponatremia (serum should not be used. Two randomized trials have shown sodium < 130 mEq / l) while on diuretics should be managed significantly lower efficacy of the loop diuretic furosem- with O uid restriction and a decrease in the dose of diuretics. ide used alone compared with spironolactone alone (143) ! ere is no evidence that other diuretics, such as metolazone, or with the combination of spironolactone /furosemide thiazides, or torsemide, o@ er an advantage over spironolactone (142) . When furosemide is used alone, sodium that is not and furosemide. re-absorbed in the loop of Henle is taken up by the distal LVP with i.v. albumin has been shown to be as e@ ective and collecting tubules because of the hyperaldosteronism as standard therapy with diuretics but with a signi$ cantly present in most cirrhotic patients with ascites. Therefore, faster resolution and the same or a lower rate of complica- furosemide should not be used as the sole agent in the treat- tions (145 – 147) . As this therapy is signi$ cantly more expen- ment of cirrhotic ascites. sive and requires more resources than the administration of As mentioned earlier, ascites therapy is not an emergency diuretics, it is reserved for patients not responding to diu- as the risk of death is not implicit unless the O uid becomes retics (see below). However, in patients with tense ascites in infected. ! erefore, the use of i.v. diuretics is not warranted as whom other complications are absent or have been resolved, it has the potential to lead to volume depletion and renal dys- it is reasonable to initiate therapy with total paracentesis function (Supplementary Table 7 ) . (i.e., removal of the maximal amount of ascites) with con-  erapies under investigation . Clonidine is a centrally act- comitant albumin infusion followed by the administration ing  2-agonist with sympathicolytic activity in cirrhosis. In of diuretics (141) . ! is therapy will accelerate the ameliora- a single-center randomized double-blind placebo-controlled tion of symptoms secondary to abdominal distension and, RCT in patients with uncomplicated ascites and an activated in those hospitalized, will accelerate the patient ’ s discharge sympathetic (as de$ ned by serum norepine- from the hospital. phrine levels >300 pg / ml), clonidine was associated with a Dose and duration . ! e preferred diuretic schedule is to initi- signi$ cantly lower number of re-admissions for ascites and a ate therapy with spironolactone alone at a single daily dose of longer time to re-admission, as well as lower requirements of 50 – 100 mg and to increase it in a stepwise manner to a maxi- LVP, spironolactone, and furosemide (150). ! ese promising mum of 400 mg / day. As the e@ ect of spironolactone takes several results require further investigation before clonidine can be days to develop, it can be administered in a single daily dose widely recommended. and the dose should be adjusted only every 3– 4 days. If weight In addition to an increasing free water excretion, selective loss is not optimal ( < 2 lb / week) or if hyperkalemia develops, inhibition of arginine vasopressin type 2 receptors (V2 recep- furosemide is then added at an initial single daily dose of 20 – tor antagonists) have a natriuretic e@ ect (151 – 153) . A phase II 40 mg and increased in a stepwise manner to a maximum of study of satavaptan, a V2 receptor antagonist, in 148 patients 160 mg / day. To minimize complications, the maximal weight with cirrhosis and ascites without hyponatremia showed a dose- loss in patients without edema is 1 lb / day (0.5 kg / day), whereas related increase in volume and a dose-related decrease in a of 2 lb / day (1 kg / day) is allowed in patients with body weight without changes in serum creatinine (154) . Fur- edema. ther analysis is required (Supplementary Table 7 ) .

© 2009 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY 1814 Garcia-Tsao et al.

Table 6 . Management strategy in uncomplicated ascites

General management Treat ascites once other complications have been treated Avoid NSAIDs Norfl oxacin prophylaxis (400 mg p.o. q.d.) in patients with an ascites protein level of < 1.5 g / dl, impaired renal function (serum creatinine level ≥ 1.2 mg / dl, BUN ≥ 25 mg / dl, serum sodium level ≤ 130 mEq/ l), or severe liver failure (CTP score ≥ 9 points with serum bilirubin level ≥ 3 mg / dl) Specifi c management Salt restriction 1 – 2 g / day REVIEW REVIEW Liberalize if restriction results in poor food intake Diuretics Spironolactone based: Spironolactone alone (start at 50– 100 mg q.d., single morning dose) or Spironolactone (50 – 100 mg q.d.) + furosemide (start at 20– 40 mg q.d., single morning dose) LVP Use as initial therapy only in patients with tense ascites; administer intravenous albumin (6– 8 g / l of ascites removed) Follow-up and goals Adjustment of diuretic dosage should be performed every 4– 7 days

Patient should be weighed at least weekly and BUN, creatinine, and measured every 1– 2 weeks while adjusting dosage

Double dosage of diuretics if: Weight loss < 4 lb (2 kg) a week and BUN, creatinine, and electrolytes are stable

Halve the dosage of diuretics or discontinue if: Weight loss ≥ 1 lb (0.5 kg / day) or if there are abnormalities in BUN, creatinine, or electrolytes

Maximum diuretic dosage is spironolactone (400 mg q.d.) and furosemide (160 mg q.d.)

BUN, blood urea nitrogen; CTP, Child– Turcotte – Pugh; i.v., intravenous; LVP, large volume paracentesis; NSAIDs, nonsteroidal anti-infl ammatory drugs; p.o., orally; q.d., once daily.

! e strategy in the management of ascites is summarized in serum sodium improved signi$ cantly in patients who received Table 6. i.v. albumin. ! us, it seems that albumin may be useful in the short term, although long-term use would seem impractical Treatment of hyponatremia in patients with cirrhosis and and expensive. ascites . D i l u t i o n a l h y p o n a t r e m i a , m a i n l y a t t r i b u t a b l e t o i m - Several randomized controlled trials suggest that selec- paired free water excretion through the non-osmotic release of tive inhibition of arginine vasopressin type 2 receptors vasopressin, is a complication that occurs in ~ 20 % of patients (V2 receptor antagonists), which increase water re-absorp- with cirrhosis and ascites (155) . It is usually tion in the distal renal nephron, are useful in ameliorat- because it develops slowly. However, recent data suggest that ing hyponatremia. Short-term placebo-controlled trials of hyponatremia is a risk factor for the development of HE and VPA-985 (lixivaptan) showed a dose-dependent improve- is associated with a poor quality of life (156) . Hyponatremia is ment in serum sodium (153,160) , with the main compli- an independent predictor of death in patients with decompen- cation being with the highest dose (250 mg sated cirrhosis (157,158) . b.i.d.) (160) . Similarly, a large multicenter trial in which Candidates . Candidates are patients with cirrhosis and ascites patients were randomly assigned to placebo (n = 2 2 3 ) o r who have a serum sodium level below 130 mEq / l. oral tolvaptan ( n = 225) at a dose of 15 mg daily showed that Accepted therapies. Besides diuretic discontinuation, the most tolvaptan, used for 30 days in patients with euvolemic or commonly accepted method for the management of hyponatremia hypervolemic hyponatremia (of whom 63 had cirrhosis), is O uid restriction of approximately 1 – 1.5 l / day; however, the e - was associated with a rapid improvement in serum sodium cacy of this approach is limited (Supplementary Table 8 ) . and significant weight loss compared with placebo (161).  erapies that should not be used. Hypertonic saline solution Finally, data from a large multicenter trial of satavaptan should not be used in these patients as hyponatremia is chronic in patients with cirrhosis, ascites, and hyponatremia indi- and is dilutional, and administration of sodium will only worsen cated that short-term (14 days) use was effective in cor- ascites and (Supplementary Table 8 ) . recting serum sodium levels in >80% of the patients who  erapies under investigation. Anti-diuretic hormone release received 25 mg / day (162) . V2 receptor antagonists are not in cirrhosis results from a decrease in e@ ective arterial blood yet approved in the United States for patients with cirrho- volume; therefore, volume expansion with albumin is a rea- sis and ascites, and their efficacy and safety should be fur- sonable alternative. In small series and a small RCT (159) , ther evaluated in long-term studies. An i.v. V1 – V2 receptor

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antagonist, conivaptan, is approved by the US FDA (Food formation of ascites, recurrence of ascites is the rule rather and Drug Administration) for the treatment of euvolemic than the exception. ! e frequency of LVPs is determined by hyponatremia in hospitalized patients; however, V1-recep- the rate of ascites re-accumulation and, ultimately, by the need tor antagonism may have a deleterious hemodynamic effect to relieve the patient’ s discomfort. In turn, the rate of ascites re- in cirrhosis (Supplementary Table 8 ) . accumulation depends largely on the patient’ s compliance with salt restriction and use of diuretics. Treatment of refractory ascites . In a p r o s p e c t i v e s t u d yrac- , r e f In patients in whom daily LVPs are being performed or in tory ascites developed in 17% of patients with cirrhosis and whom > 5 l LVPs are removed, albumin should be administered at REVIEW ascites at 5 years (163). Refractory ascites assumes either diu- a dose of 6 –8 g of albumin i.v. per liter of ascites removed (141) . retic-resistant ascites (ascites that is not eliminated even with Contraindications/ side e ects. As mentioned above, a compli- maximal diuretic therapy) or diuretic-intractable ascites (as- cation of LVP, particularly without the concomitant administra- cites that is not eliminated because maximal doses of diuret- tion of albumin, is PCD, which is characterized by a signi$ cant ics cannot be attained given the development of diuretic-in- increase in plasma-renin activity a% er paracentesis. PCD seems duced complications, such as HE, renal dysfunction, and / or to be secondary to a worsening in the vasodilatory state (122) . abnormalities) (164) . However, before diagnosing ! erefore, LVP should not be performed in the setting of con- refractory ascites, it is necessary to ascertain whether the pa- ditions that could potentially worsen the vasodilatory state of tient has adhered to the prescribed sodium-restricted diet and cirrhosis, such as SBP. has refrained from using NASIDs, which blunt the response to Alternative therapies . TIPS is considered to be a second-line diuretics. Non-adherence to dietary sodium restriction and/ or therapy for refractory ascites. ! is recommendation is based diuretics should be suspected if patients fail to lose weight de- on the results of two meta-analyses of $ ve studies compar- spite an adequate 24-h urine sodium excretion (> 50 mEq / l or ing LVP plus albumin with TIPS (168,169), which showed greater than daily sodium intake). that, as expected, recurrence of ascites a% er LVP was signi$ - Candidates . Candidates are cirrhotic patients with ascites who cantly greater in patients randomized to LVP plus albumin, fail to respond to diuretics (despite adherence to diet and drugs) but no di@ erences in mortality were observed. However, there or who present complications, which preclude the administra- was a higher rate of severe encephalopathy and a higher cost tion of adequate doses of these drugs. Recommendations for in the group randomized to TIPS. However, a subsequent patients with refractory ascites apply to patients with refractory meta-analysis of four randomized controlled trials, includ- hepatic hydrothorax, although these patients should undergo ing individual patient data indicated a signi$ cantly higher an in-hospital careful diuretic therapy before the hydrothorax transplant-free survival rate in the TIPS group vs. the LVP is considered refractory (Supplementary Table 9 ) . group (P = 0.035), without di@ erences in encephalopathy Accepted therapy. Presently, serial LVPs are the $ rst-line (170) . Although LVP is still a reasonable initial approach to therapies used for patients with refractory ascites, adding albu- the patient with refractory ascites, TIPS should be considered min if >5 l are removed at once. To increase the time between earlier on than recommended earlier (141) , e.g., in those who paracenteses, patients should continue on maximally tolerated require > 1 – 2 LVP / month. TIPS should also be considered diuretic dose provided that the urinary sodium is > 30 mEq / l. in patients in whom ascites is loculated. Although studies Otherwise, diuretics can be discontinued (141) . on TIPS for refractory ascites were carried out using uncov- Although a single 5-l LVP without albumin replacement ered stents, the use of covered stents is recommended cur- causes no disturbances in systemic and renal hemodynam- rently, because of the lower rate of shunt dysfunction and a ics (165) , daily LVP without i.v. albumin is associated with potentially lower risk of encephalopathy and mortality (171) . hyponatremia and renal impairment, complications that can Patients with serum bilirubin > 3 mg / dl, a CTP score > 11, age be prevented with the concomitant use of i.v. albumin (166) , > 70 years, and / or evidence of are at a high risk ! e need for concomitant administration of i.v. albumin was of death or shunt dysfunction, and TIPS should be avoided in further shown in a trial comparing albumin with synthetic these patients (141,172) (Supplementary Table 9 ) . plasma volume expanders. In this trial, albumin was shown Peritoneo-venous shunting (PVS) (e.g., LeVeen or Den- to be associated with a lower incidence of post-paracentesis ver shunts) is an alternative to LVP plus albumin. In two circulatory dysfunction (PCD) (18 %) compared with syn- randomized trials comparing LVP plus albumin with PVS, thetic plasma expanders (38 % for polygeline and 34 % for both procedures were shown to be equally effective, to have dextran-70) (167) . PCD is de$ ned as an increase in plasma- a similar rate of complications, and to have a comparable renin activity on the sixth day a% er paracentesis (indicating a survival rate (166,173) . Owing to its high obstruction rate, decreased e@ ective arterial blood volume). PCD is associated PVS required longer admissions for shunt revision or for with a faster re-accumulation of ascites and a signi$ cantly the management of other more serious complications. The shorter median survival time (10 vs. 17 months in patients use of PVS had been practically abandoned, because it was without PCD). considered that it would complicate liver transplant surgery Recommended treatment schedule. As LVP is a local therapy given its ability to produce peritoneal adhesions. However, that does not act on any of the mechanisms that lead to the a recent case series of pre-transplant patients showed that

© 2009 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY 1816 Garcia-Tsao et al.

Table 7 . Management strategy for refractory ascites

Defi nitions Ascites that is not eliminated even with maximum diuretic therapy Ascites that is not eliminated because maximum dosages of diuretics cannot be attained, given the development of diuretic-induced complications Recommended therapy Total paracentesis + i.v. albumin (6 – 8 g / l of ascites removed) If < 5 l of ascites is removed, a synthetic plasma volume expander may be used instead of albumin REVIEW REVIEW Continue with salt restriction and diuretic therapy as tolerated Alternative therapy TIPS for patients who require frequent paracenteses (every 1– 2 weeks) and whose CTP score is ≤ 11

Peritoneovenous shunt for patients who are not TIPS or transplant candidates

CTP, Child – Turcotte – Pugh; i.v., intravenous; TIPS, transjugular intrahepatic portosystemic shunt.

PVS is not associated with additional surgical complica- decreased plasma-renin activity and decreased ascites accumu- tions (174) and could therefore, be considered in non-TIPS lation (181,182) . ! e e cacy of vasoconstrictors in the treat- transplant candidates. ment of ascites remains to be con$ rmed in larger randomized  erapies that should not be used. In patients with refractory trials, particularly given the potential deleterious e@ ects on hepatic hydrothorax, the insertion of a should be liver function observed with the combination midodrine plus avoided as it will lead to massive O uid losses, a further deple- octreotide (182) . tion of the intravascular e@ ective volume and to renal dys- Vasodilatation has also been implicated in the pathogenesis function and has also been associated with infection and high of PCD (122) . Two small randomized studies have compared mortality (175) . terlipressin with albumin in the prevention of PCD with similar  erapies under investigation . ! ese therapies are summarized values of plasma-renin activity 4– 6 days a% er LVP (183,184) . in (Supplementary Table 9 ). Clonidine is a centrally acting  2 - However, two more recent RCTs comparing midodrine with agonist with sympathicolytic activity in cirrhosis. In a small albumin have shown contradictory results with one study pilot RCT, the administration of clonidine, at a dose of 0.075 mg showing similar e@ ects on 6-day levels of plasma-renin activ- po b.i.d., plus spironolactone to patients with refractory ascites ity (185) and another showing signi$ cantly higher rate of PCD increased natriuresis and signi$ cantly decreased plasma nore- with midodrine compared with albumin (186) . ! erefore, pinephrine and aldosterone levels, as well as plasma-renin results on the use of vasoconstrictors to prevent PCD are also activity. In a mean follow-up of 10.5 months and compared inconclusive. with patients who were treated with LVP plus albumin ( n = 10), ! e management strategy for patients with refractory ascites patients who received clonidine plus spironolactone ( n = 10) had is summarized in Table 7. less re-admissions for ascites, a longer time to ascites re-accu- mulation, and decreased spironolactone requirements (176) . Treatment of HRS . H R S i s a t y p e o f r e n a l f a i l u r e t h a t o c c u r s As mentioned earlier, V2 receptor antagonists have a natriu- in patients with cirrhosis and severe liver dysfunction and has retic e@ ect, and in a randomized double-blind placebo-control- been de$ ned as serum creatinine > 1.5 mg / dl (164,187) , although led study in 151 patients treated with LVP plus spironolactone, it has recently been suggested that it be de$ ned as per the Acute satavaptan was associated with a longer time to recurrence of Kidney Injury Network as an increase in serum creatinine of ascites requiring LVP and a signi$ cantly lower number of para- ≥ 0.3 mg / dl or increase of ≥ 150 to 200% (1.5- to 2-fold) from centeses (177) . baseline (188) . HRS is considered to be a part of the clinical Vasodilatation is one of the main mechanisms in the patho- spectrum of the cirrhotic patient with ascites and therefore, it genesis of ascites. In small studies that were carried out in non- usually occurs in patients with refractory ascites with or with- azotemic patients with cirrhosis and ascites, the short-term oral out hyponatremia. HRS has been divided into two types; HRS-1 administration of midodrine, an α -adrenergic vasoconstrictor, is a rapidly progressive type of acute renal failure and usually is associated with a signi$ cant improvement in systemic hemo- occurs in hospitalized patients, whereas HRS-2 is a slower type dynamics and consequently with decreases in plasma-renin of renal failure and mostly occurs in outpatients with refrac- activity and plasma aldosterone levels and increases in urinary tory ascites. ! e prognosis of type 1 HRS is very poor, with a sodium and creatinine clearance (178,179) . Similar bene$ cial median survival of ~ 2 weeks (133) , whereas HRS-2 has a systemic hemodynamic and renal e@ ects have been observed relatively longer median survival of ~ 6 months (189). with the acute administration of terlipressin to patients with Acute renal failure, recently renamed AKI (190) , occurs in cirrhosis and ascites (180) . ! e longer-term (4 week) admin- ~ 19 % of hospitalized patients with cirrhosis (188) . ! e most istration of midodrine plus octreotide in small numbers common cause of AKI in cirrhosis is pre-renal AKI, account- of patients with refractory ascites has been associated with ing for ~ 68 % of the cases, followed by intra-renal causes,

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such as (ATN) and glomerulonephritis outcome than those transplanted without HRS (201). A recent (32% ), with post-renal causes accounting for < 1 % of the cases study, carried out in the MELD era, shows that pre-operative (188) . HRS itself is a form of pre-renal failure, as it results from serum creatinine is an independent predictor of post-trans- vasodilatation and a marked reduction in e@ ective arterial blood plant survival (200) . ! erefore, it is important to have therapies volume leading to renal vasoconstriction (189,191) . Compared that will reduce serum creatinine and “ bridge ” the patient-to- with other forms of pre-renal AKI, HRS is not volume-respon- liver transplantation. sive and constitutes ~ 33 % of the cases of pre-renal AKI; i.e., it Bridging therapies to liver transplantation. As the mechanism accounts for only ~ 20 % of cases of AKI in hospitalized patients that drives HRS is extreme splanchnic and systemic vasodila- REVIEW with cirrhosis (188) . tation, vasoconstrictors have been used as a bridge to trans- Presently, speci$ c therapy is only recommended for patients plantation (Supplementary Table 10 ). Until recently, data with type 1 HRS, i.e., for patients with AKI that occurs rapidly using arteriolar vasoconstrictors in HRS were mostly derived over a period of < 2 weeks. Although consensus conferences from small uncontrolled studies using ornipressin, terlipressin, have required that serum creatinine levels double to a level noradrenaline, the combination of octreotide plus midodrine, >2.5 mg / dl in this period (164,187) , waiting until these levels or vasopressin. ! ese studies have been summarized recently are reached may decrease the response to speci$ c therapy (192 – and showed promise in the treatment of type 1 HRS (188) . 194) and therefore, it has been suggested that treatment for ! e best evidence supports the use of terlipressin for HRS HRS-1 should be initiated earlier, with only 1.5-fold increases and it is widely used in Europe and Asia, but it is not approved in creatinine. by the US FDA. Four RCTs (193,194,202,203) have shown that Candidates. Candidates are patients with cirrhosis and ascites HRS reversal is higher with terlipressin (46 %) compared with who develop AKI and in whom other more common causes of the control group (11% ). In the only placebo-controlled, dou- have been excluded. In a patient with cirrhosis who presents with ble-blind multicenter trial that included the largest number of sudden deterioration of renal function, one of the $ rst steps is to patients (193), HRS reversal occurred in 34 % of the patients, discontinue diuretics (or other medications that could potentially a rate signi$ cantly greater than in placebo-treated patients decrease e@ ective blood volume, such as or vasodila- (13% ). Overall survival was not improved in the two largest tors) and to expand the intravascular volume with i.v. albumin at RCTs (193,194) . However, survival is signi$ cantly improved a dose of 1 g / kg of body weight up to a maximum of 100 g (187) in patients who respond to terlipressin (193,194,204,205). or with saline solution in cases in which O uid loss from over- Two recent small, open-label RCTs that compared noradrena- diuresis is suspected (164) . Second, factors known to precipitate line with terlipressin showed that neither HRS reversal nor renal failure in cirrhosis (infection, O uid, or blood loss) need to the rate of side e@ ects was di@ erent between groups (206) . ! e be investigated, and if present, they should be treated (187) . If combination of midodrine plus octreotide has the advantage serum creatinine does not improve or continues to worsen despite of oral / subcutaneous administration (192,207) but has not these measures, the di@ erential diagnosis is between intrinsic been tested against terlipressin. In the United States, o@ -label renal failure, HRS, and post-renal failure. To rule out post-renal use of the combination of midodrine plus octreotide associ- failure, a renal ultrasound should be obtained, although this is a ated with i.v. albumin, remains a commonly used regimen rare cause of AKI in cirrhosis. To rule out intrinsic renal failure, for HRS (208) , and is supported by the AASLD treatment urinary sediment should be analyzed. Finding signi$ cant pro- recommendations (209). teinuria or hematuria suggests glomerulonephritis, and $ nding Dose and duration . Terlipressin has been used at di@ erent granular or epithelial casts suggests ATN but these $ ndings are doses in di@ erent studies. It should be started at a dose 0.5– 1 mg not de$ nitive. ! e di@ erentiation between ATN and HRS is the i.v. (slow push) every 4– 6 h. If there is no early response (>25% most di cult, as urine indices and response to volume expan- decrease in creatinine levels a% er 2 days), the dose can be dou- sion may be equivocal (188) . A history of septic or hypovolemic bled every 2 days up to a maximum of 12 mg / day (i.e., 2 mg i.v. , as well as a recent history of nephrotoxins or contrast dye every 4 h). Treatment can be stopped if serum creatinine does suggests ATN (188) . It has been suggested that the response to not decrease by at least 50 % a% er 7 days at the highest dose. vasoconstrictors plus albumin may also be used to establish this In patients with early response, treatment should be extended di@ erential (195) . until reversal of HRS (decrease in creatinine below 1.5 mg / dl) Accepted therapy . ! e $ rst and only choice for de$ nitive or for a maximum of 14 days (187) . therapy for HRS is liver transplantation, as it is the only ther- A more rational method for adjusting the dose of vasocon- apy that will provide a long-term survival ( Supplementary strictors is by mean arterial blood pressure (an Table 10 ). With the implementation of the MELD (model for indirect indicator of vasodilatation). ! is method has been used end-stage liver disease) score in the allocation of organs in the for adjusting the dose of midodrine plus octreotide (207,208) . United States, priority for transplant is given to patients with ! e doses of octreotide and midodrine are titrated to obtain high creatinine (196) . Patients with HRS who are transplanted an increase in the mean arterial pressure of at least 15 mm Hg. have more complications and a higher in-hospital mortality Midodrine is administered orally at an initial dose of 5 – 7.5 mg rate than those without HRS (197 – 200) . However, patients who thrice daily and, if necessary, increased to 12.5 – 15 mg thrice respond to vasoconstrictor therapy (see below) have a similar daily. Octreotide is administered subcutaneously at an initial

© 2009 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY 1818 Garcia-Tsao et al.

Table 8 . Diagnosis and management strategy of hepatorenal syndrome

Diagnosis Consider HRS in a patient with cirrhosis and ascites and a creatinine level of > 1.5 mg / dl It is a diagnosis of exclusion; before making the diagnosis, the following need to be ruled out and treated: Sepsis (patient needs to be pancultured) Volume depletion (hemorrhage, , overdiuresis) Vasodilators Organic renal failure (urine sediment, kidney ultrasound)

REVIEW REVIEW Diuretics should be discontinued and intravascular volume expanded with i.v. albumin If renal dysfunction persists despite above, diagnose HRS Recommended therapy Liver transplant (priority dependent on MELD score) If patient is on transplant list, MELD score should be updated daily and communicated to transplant center; if patient is not on transplant list, packet should be prepared urgently Alternative (bridging Vasoconstrictors Octreotide 100 – 200 mcg s.c. t.i.d. Goal to increase MAP by therapy) PLUS 15 mm Hg Midodrine 5 – 15 mg p.o. t.i.d. or Terlipressina 0.5 – 2.0 mg i.v. every 4 – 6 h and Intravenous albumin 50 – 100 g i.v. q.d. (both for at least 7 days) i.v., intravenous; HRS, hepatorenal syndrome; MAP, mean arterial pressure; MELD, model for end-stage liver disease; t.i.d.; thrice a day; s.c., subcutaneously; p.o., orally a Not available in the United States.

dose of 100 μ g thrice daily and, if necessary, increased to 200 μ g combination of peripheral vasoconstrictors plus renal vasodila- thrice daily (207) . tors has also failed to improve renal function in patients with  erapies under investigation . Small uncontrolled studies HRS (218) . suggest that the TIPS may be useful in the treatment of type A recent trial compared the e@ ects of i.v. octreotide infusion 1 and type 2 HRS (210,211); however, the majority of patients (50  g / h) plus albumin with placebo using a randomized, dou- in these trials had alcoholic cirrhosis and many were actively ble-blind, cross-over design (219) . A% er 4 days of continuous drinking and therefore, the improvement observed could have infusion (octreotide or placebo) plus albumin, there was no resulted from an improvement in the underlying liver disease. improvement in renal function, urinary sodium, or plasma- Interestingly, a recent uncontrolled trial of TIPS placed in renin activity, leading to the conclusion that octreotide alone $ ve patients with HRS-1 who had responded to octreodide / is ine@ ective in the treatment of HRS in cirrhotic patients midodrine, showed that TIPS was associated with long-term (Supplementary Table 10 ) . success with increased glomerular $ ltration rate and sodium ! e strategy in the diagnosis and management of HRS is excretion (192) . TIPS should be used as a treatment of type I summarized in Table 8. HRS only in the setting of prospective randomized controlled trials (Supplementary Table 10 ) . Treatment of HE In a small, randomized study, the molecular adsorbent recir- H E r e O ects a spectrum of neuropsychiatric and psychometric culating system (MARS), a modi$ ed method using an test performance abnormalities occurring in patients with sig- albumin-containing dialysate, was shown to improve the 30- ni$ cant liver dysfunction a% er exclusion of other known neu- day survival in 8 patients with HRS-1 compared with 5 patients ropsychiatric diseases. HE represents a continuum from minimal treated with intermittent venovenous hemo$ ltration alone (sub-clinical) to overt HE with varying degrees of severity (220) . (212) . As MARS incorporates a standard dialysis machine or a In a consensus conference, HE was further divided into episodic continuous venovenous hemo$ ltration monitor and glomerular HE de$ ned as acute episodes with or without (spontaneous) an $ ltration rate was not measured, the decrease in serum creati- identi$ able precipitating factor; recurrent HE when 2 episodes nine observed in most patients could be related to the dialysis of episodic HE occur within 1 year; persistent HE that includes process. However, clear bene$ cial e@ ects on systemic hemody- persistent cognitive de$ cits that a@ ect negatively on social and namics and on HE were observed. MARS is still considered to be occupational functioning, or HE that recurs promptly a% er dis- an experimental therapy and its use in patients with type-1 HRS continuing . Minimal HE (that used to be referred cannot be recommended outside prospective pathophysiologi- to as “ sub-clinical ” encephalopathy) is the asymptomatic phase cal or therapeutic investigations (Supplementary Table 10 ) . that is diagnosed on the bases of abnormal psychometric testing  erapies of proven ine& cacy. Renal venodilators, such as (220) and will not be discussed in this section. prostaglandins and dopamine (at non-pressor doses), have been ! e diagnosis of HE is established most frequently on used in patients with HRS in an attempt to reduce intra-renal clinical grounds by the identi$ cation of compatible symp- vascular resistance, without an obvious bene$ t (213 – 217) . ! e toms a% er excluding alternative causes, but may rarely involve

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formal psychometric testing, electroencephalograms, or neuro- In a landmark study, Fessel and Conn (227) showed that of imaging. 100 patients with (episodic) HE, 80 % of the cases were pre- Treatment of HE is based on several leading hypotheses on cipitated by factors, such as GI hemorrhage, increased protein the underlying pathophysiology of HE (221). ! e intake, infection (including SBP), pre-renal , hypoka- hypothesis is the prevalent hypothesis based on the observa- lemic , hyponatremia, , , or the use tions that increased serum ammonia levels are observed in 60 – of and tranquilizers. Accordingly, the $ rst step in the 80 % of patients with HE, and that reducing ammonia through treatment of episodic HE is the identi$ cation and treatment of decreased production or increased removal leads to clinical the precipitant cause (Supplementary Table 11 ) . REVIEW improvement. ! e accumulation of in brain astro- Regarding speci$ c therapy for HE, lactulose is the treatment cytes induced by produces osmotic stress of choice given its established safety and e@ ectiveness. Lactu- and causes to swell and malfunction. Hyponatremia, lose is a non-absorbable disaccharide that reduces ammonia by a $ nding common in advanced cirrhosis, seems to aggravate acidifying the colon and reducing colonic transit time. A large this swelling and may be a factor that aggravates HE (222) . systematic review showed that lactulose or lactilol was more Normally, portal vein ammonia produced by small bowel ente- e@ ective than placebo in treating HE (relative risk 0.62, 95% CI: rocytes or through colonic bacterial catabolism of nitrogen 0.46 – 0.84) without di@ erences in mortality (228) . Oral admin- sources (e.g., ingested protein), is metabolized and cleared by istration is preferred, although lactulose may be used in the liver. In cirrhosis, ammonia is not cleared by the liver as patients who are unable to consume it orally (Supplementary it escapes through the portosystemic shunts and because an Table 11 ) . impaired liver fails to perform this function. ! e gamma-amino Dose and duration . Lactulose should be administered ini- butyric acid (GABA) hypothesis suggests that the GABA- tially at a dose of 30 ml every 1 – 2 h until a bowel movement receptor complex (GABA-binding site, chloride channel, and occurs. A% er catharsis begins, the oral dose should be adjusted barbiturate and receptor sites) is an important to obtain 2 – 3 so% bowel movements per day (15 – 30 ml b.i.d.). neuronal inhibitor, and that GABA-ergic transmission interacts Lactulose enemas (300 ml in 1 l of water) should be adminis- with ammonia in the pathogenesis of HE. ! e false neurotrans- tered every 6– 8 h until the patient is awake enough to start oral mitter hypothesis suggests that HE may stem from an increased intake. Lactulose can be discontinued once HE is resolved in ratio of plasma aromatic amino acids to branched-chain amino patients in whom a precipitant was identi$ ed and treated and in acids that lead to increased levels of monoamine neurotrans- patients without an obvious precipitant but who do not have an mitters, which contribute to altered neuronal excitability. earlier history of HE. Lactulose should be continued in patients ! e approach to HE therapy varies according to the clinical with recurrent or persistent HE (see below). setting, e.g., episodic vs. persistent (220) . As the development of Side e ects . ! e common side e@ ects of lactulose therapy HE is not lethal by itself, management is focused on the treat- include unpleasant taste, , abdominal cramps, and ment of overt HE rather than its prophylaxis; although HE can diarrhea. Lactulose should be withheld when diarrhea occurs, be prevented by limiting exposure to common precipitants and restarted at a lower dose once it resolves. It should be (e.g., sedatives). emphasized that diarrhea itself may be more harmful than HE, as it may result in a decreased e@ ective arterial volume and Episodic HE . ! e major goals of treatment include the iden- precipitate renal dysfunction. Another harmful consequence of ti$ cation and correction of precipitating factors, as well as lactulose-induced diarrhea is that has recently measures aimed at reducing the brain concentration of ammo- been associated with a high mortality in cirrhosis (158) . nia (223,224) . Protein-restricted diets are usually prescribed. Alternative therapies . Antibiotics reduce ammonia load by However, their e cacy was recently evaluated in a trial car- eliminating colonic bacteria. , a poorly absorbed ried out in cirrhotic patients admitted to the hospital owing aminoglycoside, has been used in the treatment of HE, com- to an episode of acute encephalopathy (n = 30), which rand- bined with sorbitol or milk of magnesia (to accelerate intestinal omized patients to receive a low-protein diet with progressive transit and to cleanse the bowel), and has been shown to be as increments or a normal protein diet for 14 days, in addition to e@ ective as lactulose (229) . However, long-term use has been standard measures for treating HE. ! e outcome of HE was not associated with nephrotoxicity and ototoxicity, limiting its use. signi$ cantly di@ erent between both study groups. Protein syn- dosed at 200 mg four times a day (q.i.d.) has also thesis was similar for low and normal protein diet, but those of been shown to be as e@ ective as neomycin dosed at 1 g q.i.d., the low-protein diet group showed higher protein breakdown but may be associated with . is (225) . As mentioned in an accompanying editorial, the ration- a non-absorbed derivative of with a broad-spectrum ale for a low-protein diet in the short- and long-term manage- antibiotic activity against gram-positive and gram-negative ment of HE seems questionable as it is of no bene$ t and could organisms. It has been approved by the FDA for the treatment of be detrimental to the patient with cirrhosis (226) . travelers’ diarrhea due to non-invasive , and has Accepted therapy . ! e most important facts to be recognized been given orphan status for HE. Two RCTs performed outside are that (i) HE is reversible, and (ii) a precipitant cause can be the United States have shown that rifaximin, at a dose of 400 mg identi$ ed in the majority of patients. po thrice daily, is as e@ ective as (230) or lactulose (231)

© 2009 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY 1820 Garcia-Tsao et al.

in episodic HE. A recent meta-analysis showed that rifaximin is not superior to non-absorbable disaccharides in the treat- Table 9. Management strategy of episodic hepatic encephalopathy (HE) ment of episodic or persistent HE, except that it may be better tolerated (232) . Results were the same in a sensitivity analysis, General management Identify and treat precipitating factor (GI including only patients with acute (episodic) encephalopathy. hemorrhage, infection, pre-renal azotemia, constipation, sedatives) ! erefore, and until the results of ongoing larger trials are Short-term ( < 72 h) protein restriction may be available, rifaximin should be restricted to patients who have considered in severe HE

REVIEW REVIEW not responded to lactulose or in patients who cannot tolerate Specifi c therapy Lactulose enemas (300 cm 3 in 1l of water) in even the minimal dose of lactulose (Supplementary Table 11 ) . patients who are unable to take it p.o. ! ere is no evidence to suggest that combining rifaximin and or lactulose will be of further bene$ t and it could be potentially Lactulose 30 cm 3 p.o. every 1 – 2 h until bowel detrimental, as rifaximin will eliminate bacteria that metabo- evacuation, then adjust to a dosage that will lize lactulose and acidify the colon. result in 2 – 3 formed bowel movements per  erapies under investigation. Various therapies directed at day (usually 15 – 30 cm 3 p.o. b.i.d.) reversing alterations of various postulated in Lactulose can be discontinued once the the pathogenesis of HE (such as bromocriptine and O umaze- precipitating factor has resolved nil), or in the (such as ornithine aspartate and ben- b.i.d., twice a day; GI, gastrointestinal; p.o., orally. zoate) have been investigated and shown in limited trials to be useful in the treatment of HE (221,223) . Regarding O umazenil, a benzodiazepine receptor antagonist, two recent meta-analy- Side e ects . ! e common side e@ ects of lactulose therapy ses showed a bene$ cial e@ ect on HE. One of them showed a include unpleasant taste, bloating, abdominal cramps, and signi$ cant clinical and electroencephalographic improvement diarrhea. Lactulose should be withheld when diarrhea occurs, of HE in patients treated with O umazenil from 5 min to 3 days and restarted at a lower dose once it resolves. It should be (233) . ! e other showed that, although O umazenil had no sig- emphasized that diarrhea itself may be more harmful than HE, ni$ cant e@ ect on recovery or survival from HE, it was associ- as it may result in decreased e@ ective arterial volume with con- ated with a signi$ cant improvement in HE at the end of the sequent hypernatremia and / or renal dysfunction. treatment (234) . Until further evidence is available, O umazenil  erapies that should not be used. In the past, prolonged dietary may be considered for patients with chronic liver disease and protein restriction was recommended in HE, but the supporting HE, particularly for those in whom sedatives play a role or in data for this recommendation are unclear. Protein and energy whom there is no clear precipitant (Supplementary Table 11 ) . malnutrition is common in patients with cirrhosis. Protein restric- A non-conventional way of reducing ammonia is by the use tion can promote protein degradation, and if maintained for long of the MARS. In contrast to the regular methods of hemo$ ltra- periods, worsens the nutritional status and decreases muscle mass. tion, this system is designed to remove both low- and middle- Skeletal muscle is capable of decreasing blood ammonia by metab- molecular-weight water-soluble substances (such as ammonia) olizing ammonia to glutamine; therefore, measures that decrease and albumin-bound molecules. In a multicenter RCT com- muscle mass in a patient with cirrhosis should be avoided. Recent paring MARS with standard medical therapy in patients with guidelines from nutritionists no longer recommend protein restric- severe cirrhosis and grades 3 – 4 HE, MARS was associated with tion in any patient with HE (236) (Supplementary Table 12). ! e earlier and more frequent improvement of HE (235). suggested protein intake in cirrhotics (with or without HE) is 1 – ! e strategy in the management of episodic HE is summa- 1.5 g / kg / day. It has been suggested that from vegetables and rized in Table 9. dairy products give a higher calorie per nitrogen ratio and hence, produce less ammonia than animal proteins. Diet supplementation Recurrent or persistent HE . A s m e n t i o n e d a b o v e , r e c u r r e n t with amino acids (mainly branched-chain amino acids) and trace HE is when 2 episodes of episodic HE occur within 1 year; elements may improve the nutritional status and HE (237). persistent HE is de$ ned by persistent cognitive de$ cits that af- Cirrhotic patients are highly susceptible to the e@ ect fect negatively on social and occupational functioning, or HE of and doses considered therapeutic are able that recurs promptly a% er discontinuing medication. ! ese to precipitate stages of prolonged or near . ! erefore, patients require chronic therapy. One of the most common benzodiazepines and other sedative drugs (anti-histamines, causes of persistent HE is TIPS placement. Persistent and in- , and anti-depressants with sedative e@ ects) should be tractable post-TIPS HE can be treated by occluding the shunt avoided or administered very carefully and at lower doses in or by reducing its diameter. cirrhotic patients. Eradication of Helicobacter pylori, a - Accepted therapy . Lactulose is the treatment of choice, given its producing bacteria found in the upper GI tract, has not been established safety and e@ ectiveness (Supplementary Table 12 ) . shown to be helpful in the treatment of HE. Dose and duration. Lactulose should be administered orally A randomized, but not blinded, study that compared lactitol at a dose adjusted to obtain 2 – 3 so% bowel movements per day 60 g / day (n = 25), rifaximin 1,200 mg /day, and no-treatment in (starting at 15 ml po b.i.d.). the prevention of post-TIPS HE showed no di@ erences in the

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in the VA system has been reported (243) . Recommenda- Table 10 . Management strategy of persistent hepatic tions stated below follow recent treatment recommendations encephalopathy (HE) endorsed by the AASLD (244) . General management No long-term protein restriction Protein from dairy or vegetable sources is Surveillance preferable to animal protein Avoid sedatives and tranquilizers Surveillance for HCC is indicated for all patients with a diag- Avoid constipation nosis of cirrhosis, particularly those due to hepatitis C infec-

tion or alcohol, which are the most common risk factors in the REVIEW Specifi c therapy Lactulose dosage that produces 2– 3 soft, formed bowel movements per day, starting at United States, and selected non-cirrhotic patients with hepa- 15 – 30 cm 3 p.o. b.i.d. titis B, including Asian females aged ≥ 50 years (males aged Alternative therapy Rifaximin 400 mg p.o. t.i.d. in patients who ≥ 40 years), Africans over the age of 20 years, and those with cannot tolerate lactulose a family history of HCC (Supplementary Table 13 ). A com- bination of serum α -fetoprotein plus abdominal ultrasound b.i.d., twice a day; p.o., orally; t.i.d., thrice a day. every 6 – 12 months is the recommended approach for HCC surveillance, based on average doubling times that average 6 1-month incidence of HE (36, 32, and 32% , respectively) (238) months, and studies showing improved survival, such as a large and therefore, prophylactic therapy in patients in whom TIPS RCT of surveillance with α -fetoprotein and ultrasound every is performed is not warranted. 6 months vs. no surveillance in a cohort of 18,816 patients in  erapies under investigation. Recently, there has been an China that showed a 37 % reduction in HCC-related mortality increase in the use of rifaximin because it seems to be safer (245) and a small study in US veterans showing that screened than neomycin and was shown to be as e@ ective as lactitol patients were 10 times more likely to have received potentially in episodic HE (230); however, rifaximin is costly. In fact, a curative treatment which in turn led to an improvement in cost-e@ ective study showed that rifaximin monotherapy was survival (243) . not cost-e@ ective in the treatment of persistent HE, although a strategy using rifaximin in patients who are lactulose- Diagnosis refractory may be highly cost-e@ ective (239) . A recent meta- ! e diagnosis of HCC is based primarily on abdominal imag- analysis showed that rifaximin is not superior to non-absorb- ing studies, and may be supported by serum tumor markers able disaccharides in the treatment of episodic or persistent or pathology. As per the recent AASLD recommendations HE, except that it may be better tolerated (232) . Results were (244) , small mass lesions ( < 1 cm) identi$ ed on ultrasound the same in a sensitivity analysis, including only patients with should be followed by a surveillance ultrasound every 3 chronic (persistent) encephalopathy. ! erefore, and until the months, and if stable over 1 –2 years, surveillance should results of ongoing trials are available, rifaximin should be return to every 6– 12 months. If mass lesions measuring restricted to patients who have not responded to lactulose or 1 – 2 cm in diameter on ultrasound are found, two dynamic in patients who cannot tolerate even the minimal dose of lactu- imaging studies (computed tomography and magnetic reso- lose. ! ere is no evidence to suggest that combining rifaximin nance imaging) should be carried out. If both show a typical and lactulose will be of further bene$ t and it could be poten- vascular pattern (arterial phase enhancement with venous tially detrimental as rifaximin will eliminate bacteria, which phase washout), the lesion should be treated as HCC. If one metabolize lactulose and acidify the colon (Supplementary or both show an atypical vascular pattern, imaging-guided Table 12 ) . can be considered to con$ rm HCC, and close surveil- Other novel therapies for HE that require further investiga- lance every 3 months is maintained if biopsy is non-diagnos- tion are synbiotic therapy (combination pro- and pre-biotic), tic. If mass lesions measuring >2 cm are found on ultrasound, which has been shown to improve minimal HE (240,241) one dynamic study (computed tomography or magnetic res- ( Supplementary Table 12 ) . onance imaging) should be obtained, and the mass should ! e strategy in the management of recurrent / persistent HE is be treated as HCC if a typical vascular pattern is observed. summarized in Table 10. However, if the serum α -fetoprotein is >200 ng /ml, biopsy is not required. A careful consideration of local expertise in imaging techniques, imaging-guided biopsy, and histopatho- SCREENING, DIAGNOSIS, AND MANAGEMENT OF logic examination is important for clinicians in determining HCC the best approaches needed to diagnose HCC. Although core HCC is an increasingly common complication of chronic biopsy specimens are preferred, imaging-guided or endo- liver disease in the United States. Population studies suggest a scopic ultrasound-guided $ ne needle aspiration cytology rising incidence of HCC from 1.4 per 100,000 between 1975 may be considered as an alternative approach on the basis of and 1977 to 3.0 per 100,000 between 1996 and 1998 (242), local expertise (246,247) . which will likely peak in the next decade. A corresponding ! e diagnostic workup of a liver mass in a patient with increase in the number of cases being diagnosed and treated chronic liver disease is summarized in Table 11.

© 2009 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY 1822 Garcia-Tsao et al.

Table 11 . Diagnostic workup of a liver mass in a patient with chronic liver disease

Mass < 1 cm Diagnosis Low likelihood of being HCC, therefore no specifi c diagnostic tests Follow-up Repeat imaging study every 3 months If no growth in 1– 2 years, no HCC; continue screening every 6 months If growth, treat as HCC Mass 1– 2 cm Diagnosis Two dynamic imaging studies Both with typical vascular Treat as HCC

REVIEW REVIEW (US, CAT scan, or MRI) pattern One typical and the other Consider biopsy of mass atypical Both atypical Consider biopsy of mass vs. close follow-up Follow-up after biopsy Biopsy confi rms HCC Treat as HCC Non-diagnostic Repeat imaging study every 3 months: If no growth in 1 – 2 years → no HCC If growth, treat as HCC Mass >2 cm Diagnosis One dynamic imaging study Typical vascular pattern Treat as HCC (US, CAT scan, or MRI) Atypical vascular pattern Biopsy of mass Follow-up after biopsy Biopsy confi rms HCC Treat as HCC Non-diagnostic Repeat imaging study every 3 months: If no growth in 1 – 2 years → no HCC If growth, treat as HCC

CAT, computerized axial tomography; HCC, hepatocellular carcinoma; MRI, magnetic resonance imaging; US, ultrasound.

Staging Approved, potentially curative therapies. Surgical resection is Once a diagnosis of HCC is established, tumor staging is the optimal therapy for solitary HCC in non-cirrhotic patients. important in guiding treatment decisions. ! e BCLC (Bar- Non-cirrhotic HCC is less common in the United States, but celona Clinic ) system is the most commonly is more frequently seen in Asia where chronic is used staging system in clinical practice, and incorporates the leading etiology. Owing to the advances in selection crite- three clinical parameters (248) : (i) tumor staging based on the ria and surgical techniques, surgical mortality is < 1 – 3 % and American Liver Tumor Study Group ’ s modi$ ed TNM (tumor- a 5-year survival a% er resection may exceed 50% . Inclusion of node-metastasis) staging system; (ii) liver function and disease patients with normal serum bilirubin and the absence of clin- severity based on CTP and MELD scores; and (iii) perform- ically signi$ cant portal hypertension (HVPG < 10 mm Hg) ance status based on World Health Organization (WHO) cri- results in excellent surgical outcomes without post-operative teria. A careful consideration of the e@ ect of HCC treatment decompensation and an improved 5-year survival of > 70 % , on quality of life and should be incorporated whereas patients with increased bilirubin and clinically signif- into the treatment approach. icant portal hypertension (HVPG ≥ 10 mm Hg) have a 5-year survival of < 30 % (249,250) . Despite the authors ’ conclusions, Treatment a recent study con$ rms that in patients with CTP class A and a Several approaches to the treatment of HCC are commonly used single tumor, indirect evidence of clinically signi$ cant portal and therefore, speci$ c treatment decisions should be based on hypertension (esophageal varices, platelet count of < 100,000 / local or regional expertise, and where available, should involve m m 3 + splenomegaly) is associated with a poor post-resection a multidisciplinary team of specialists in , surgery, 5-year survival (56% ) compared with patients without evi- liver transplantation, interventional radiology, oncology, and dence of portal hypertension (71% ) (251) . As such, assess- pathology. Treatment options include surgical resection, liver ment of clinically signi$ cant portal hypertension is important transplantation, radiofrequency ablation (RFA), transarterial in determining the eligibility for tumor resection. ! erefore, chemoembolization (TACE), and systemic , or resection is typically reserved for CTP class A or B patients combinations of these. For patients with decompensated cir- with normal bilirubin and absence of clinically signi$ cant rhosis, liver transplantation represents the treatment of choice portal hypertension with solitary HCC < 5 cm in diameter in for solitary HCC < 5 cm or early multifocal HCC (up to 3 a favorable anatomic location. Post-resection tumor recur- lesions of ≤ 3 cm each). A comparative assessment of treatment rence is common, occurring in ~70 % of individuals at 5 years, e cacy between HCC therapies in cirrhotic patients should be primarily because of true recurrence (50– 70 % ) or owing performed on the basis of survival. to the development of de novo tumors (30– 50 % ). Pre- or

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post-resection adjuvant chemotherapy has not been shown to HCC is characterized by profound neo-angiogenic activity, be e@ ective in reducing recurrence rates and therefore, is not which is dependent on the hepatic artery for its blood supply. routinely recommended. Selective arterial obstruction of targeted lobar and segmen- Liver transplantation is the preferred treatment for patients tal branches of the hepatic artery using chemotherapeutic w i t h d e c o m p e n s a t e d c i r r h o s i s w h o h a v e s o l i t a r y H C C < 5 c m agents (e.g., cisplatin or adriamycin) mixed with lipiodol and or up to 3 lesions of ≤ 3 cm each, without evidence of vascular other agents (e.g., gelfoam) result in ischemic tumor necrosis. invasion or extrahepatic spread, based on Milan criteria. ! ese Although TACE results in signi$ cant tumor necrosis in > 50 % individuals show an excellent 5-year survival of >70 % (252) . of patients, as measured by intra-tumoral necrotic “ bubbles, ” REVIEW Transplant-eligible patients in the United States who meet and has been shown to improve survival compared with no the Milan criteria are given a bonus MELD score of 22, which therapy in patients with advanced HCC and compensated may increase by 10% for every 3 months on the wait list (253) . liver disease, complete responses are uncommon. ! erefore, Unfortunately, because of limited liver donor supply, many repeat TACE sessions are frequently required (257) . TACE individuals may drop out from new contraindications to trans- is contraindicated in patients with decompensated cirrho- plantation (e.g., tumor growth, vascular invasion), while on the sis, or with portal vein obstruction. Post-embolization syn- waiting list and therefore, much enthusiasm has been gener- drome represents a unique complication of TACE occurring ated by e@ orts to use pre-transplant HCC therapy (e.g., RFA, in ~ 50 % of patients following the procedure and is typically TACE) to treat or “ downstage ” tumors, or to extend transplant marked by a self-limited 24 – 48 h period of fever, abdominal listing for tumors beyond the Milan criteria. However, existing pain, and . data are inadequate to make a recommendation for or against Systemic chemotherapy is a non-curative treatment strategy these strategies and therefore, these should be carefully consid- generally reserved for patients with advanced, unresectable ered in consultation with an experienced transplant center. Liv- HCC who are not eligible for percutaneous ablation or TACE. ing donor liver transplantation may represent one strategy to Due in part to frequent expression of drug resistance genes, reduce the drop-out rate on the wait list, and early studies sug- HCC is poorly responsive to traditional chemotherapy agents gest 5-year survival rates as high as 68 % in patients with HCC, (e.g., gemcitabine, cisplatin, doxorubicin, oxaliplatin) and does with a markedly decreased waiting time of 83 days when com- not respond to systemic hormonal therapy (e.g., tamoxifen). pared with 414 days for deceased-donor transplantation (254) . ! erefore, this type of chemotherapy should not be used in Although this is an attractive alternative, additional evidence these patients. is needed before formal recommendations on its role in HCC Molecularly targeted therapy has emerged as an impor- therapy can be established. tant new treatment approach based on an enhanced under- Percutaneous ablation is the preferred treatment for patients standing of the role of vascular endothelial growth factors with early stage HCC who are not eligible for tumor resection. (such as VEGF) and their pathways in the regulation and ! ere are two approaches that are frequently used, including tumorigenesis of HCC. is an oral multi-targeted percutaneous injection (PEI) and RFA. PEI is a highly tyrosine kinase inhibitor, which blocks HCC angiogenesis e@ ective, safe, and inexpensive approach for small HCC, which through the inhibition of both VEGF and the Raf kinase achieves necrosis rates of 90 – 100 % for tumors of < 2 cm, and in pathway. Sorafenib represents the only FDA-approved patients with compensated cirrhosis results in a 5-year survival chemotherapy agent for advanced HCC, on the basis of a of 50% , comparable with surgical resection. However, success large randomized controlled multicenter trial involving 602 rates are lower for larger tumors, with necrosis rates of 70% for patients who were randomized to a daily oral intake of sor- tumors of 2 – 3 cm, and 50 % for tumors of 3 – 5 cm (255 – 257) . afenib 400 mg or to placebo (258) . Nearly all patients had PEI is limited primarily by its inability to achieve complete preserved liver function (95 % CTP class A) and most had necrosis in tumors of ≥ 3 cm, and the need for multiple injection advanced HCC (37.8 % TNM stage 3 and 50.8 % TNM stage sessions due to an inability to access the entire tumor volume. 4). Compared with placebo, patients on sorafenib experi- RFA involves the insertion of single or multiple electrodes that enced a significantly longer median survival (10.7 vs. 7.9 deliver heat to tumor in a directed manner, inducing a wider months) and a delayed time to radiological progression. and more predictable span of tumor necrosis than PEI. As such, Major side effects observed included diarrhea (11 vs. 2 % ), RFA is equally e@ ective as PEI for small tumors of < 2 cm, but hand– foot skin reaction (8 vs. 1 %), and fatigue (15 vs. 10 %). is more e@ ective than PEI for larger tumors, for which rand- These results were recently confirmed in a similar group omized controlled trials have shown better tumor necrosis of 266 patients with HCC from the Asia – Pacific region, in and improved survival (255,257) . RFA is limited primarily by whom sorafenib was associated with a significantly longer a small but higher rate of complications (e.g., pleural e@ usions survival (2.8 vs. 1.4 months) and a decreased time to pro- and peritoneal bleeding) and by a signi$ cantly higher cost. gression (259) . Therefore, sorafenib is recommended in Approved, non-curative therapies. TACE is the preferred patients with advanced HCC not eligible for locoregional non-curative treatment for patients with large or multifo- therapy and who have preserved liver function and per- cal HCC who are not eligible for resection or percutaneous formance status. The strategy in the management of HCC is ablation, and who do not have an extrahepatic tumor spread. summarized in Table 12 .

© 2009 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY 1824 Garcia-Tsao et al.

Table 12 . Management strategy of HCC based on CTP class, size, and performance status

CTP A, PS 0 Single HCC < 2 cm HVPG < 10 mm Hg and Surgical resection bilirubin < 1.5 mg / dl Varices / collaterals or HVPG Liver transplant evaluation > 10 mm Hg or bilirubin > 1.5 mg / dl RFA / PEI CTP A – B, PS 0– 2 Single HCC 2– 5 cm HVPG < 10 mm Hg and Surgical resection

REVIEW REVIEW bilirubin < 1.5 mg / dl Varices / collaterals or HVPG Liver transplant evaluation > 10 mm Hg or bilirubin > 1.5 mg / dl RFA / PEI 2 or 3 HCC masses < 3 cm (the largest) Liver transplant evaluation Radiofrequency ablation Intermediate stage (multinodular , PS 0) Transarterial chemoembolization Advanced stage (portal invasion, metastases) Sorafenib CTP C, PS > 2 Terminal stage

CTP, Child– Turcotte –Pugh; HCC, hepatocellular carcinoma, HVPG; hepatic venous pressure gradient; PEI, percutaneous ethanol injection; PS, performance status; RFA, radiofrequency ablation.

CONFLICT OF INTEREST 9 . D ’ A mico G , P a g l i a r o L , B o s c h J . P h a r m a c o l o g i c a l t r e a t m e n t o f p o r t a l h y p e r - tension: an evidence-based approach . Semin Liv Dis 1999 ; 19 : 475 – 5 0 5 . Guarantor of the article: Guadalupe Garcia-Tsao, MD. 1 0 . C h e n W , N i k o l o v a D , F r e d e r i k s e n S L et al. B e t a - b l o c k e r s r e d uce mortality Speci! c author contributions: Guadalupe Garcia-Tsao was in cirrhotic patients with oesophageal varices who have never bled (Co- chrane review) . J Hepatol 2004 ; 40 (Suppl 1) : 67 (abstract) . responsible for writing all sections, except the ones on HE 1 1 . M e r k e l C , M a r i n R , A n g e l i P et al. 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