portal hypertension: diagnosis and management with particular reference to variceal hemorrhage

Review

Portal hypertension: Diagnosis and management withparticular reference to variceal hemorrhage

William CAREY

Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio, USA

Portal hypertension is a cause a major luminal guthemorrhage, most often from esophageal varices.Identification of those with varices, and administra-tion of therapies to reduce the likelihood of initialbleeding improve patient outcomes. Beta blockertherapy or variceal band ligation are most often used

in this context. Management of acute variceal hemor-rhage (including routine use of antibiotics) is fol-lowed by initiating strategies to reduce the frequencyof recurrent bleeding. Mortality from portal hyperten-sive bleeding has been diminished by use of theseinterventions.

KEY WORDS: band ligation, beta blocker, esophageal varice, portal hypertension, TIPS.

Portal hypertension associated with cirrhosis posesdistinctive risks, including luminal gut bleeding,ascites and hepatic encephalopathy. Bleeding is themost feared and lethal complication and will be high-lighted here. Portal hypertension is characterized byprolonged elevation of portal venous pressure(normal = 2–5 mm Hg). Minor elevations of portalpressure (6–10 mm Hg) do not result in esophagealvarices but higher pressures may. Variceal hemorrhagemay occur when portal pressure exceeds 12 mm Hg.1

By tradition the hepatic sinusoid is the reference pointin the classification of portal hypertension as denotedin Table 1, which identifies conditions associated withportal hypertension.cdd_473 25..32

PREVALENCE AND RISK FACTORS

Cirrhosis is the most common cause of portal hyper-tension in many parts of the world. Schistosomiasis is

a common cause in endemic areas. A major cause ofcirrhosis-related morbidity and mortality is the devel-opment of variceal hemorrhage, a direct consequenceof portal hypertension. Variceal hemorrhage may belethal, although effective interventions have resultedin a threefold decrease in mortality over the past threedecades. In one study mortality between 1980 and2000 decreased from 9 to 0% in Child–Pugh class Apatients, from 46% to zero in Child–Pugh B patientsand from 70 to 30% in Child–Pugh C patients.2 Muchof this improvement has resulted from more effectiveinterventions before, during and after a bleedingepisode.3

PATHOPHYSIOLOGY AND NATURAL HISTORYOF ESOPHAGEAL VARICES

Portal venous pressure is determined by portal bloodflow volume and portal vascular resistance. An inter-play of pathophysiological processes is responsible foralterations of portal pressure. Vascular obliteration bythe architectural distortion of the liver secondary tofibrous tissue and regenerative nodules are magnifiedby reversible components. Activated stellate cells arelocated perisinusoidaly in the space of Disse and have

Correspondence to: William CAREY, Cleveland Clinic Lerner Collegeof Medicine, Cleveland, OH, 44195, USA. Email: [email protected]© 2011 The AuthorJournal of Digestive Diseases © 2011 Chinese Medical AssociationShanghai Branch, Chinese Society of Gastroenterology, RenjiHospital Affiliated to Shanghai Jiaotong University School ofMedicine and Blackwell Publishing Asia Pty Ltd.

Journal of Digestive Diseases 2011; 12; 25–32 doi: 10.1111/j.1751-2980.2010.00473.x

25

contractile properties. In cirrhosis, stellate cells exhibitincreased proliferation, collagen production andincreased contractility. They respond to a variety ofvasoactive substances. Increased vascular tone incirrhosis is due to the increased production andincreased response to vasodilators and decreased pro-duction and response to vasoconstrictors such as nitricoxide, which act on the stellate cells.1 Another revers-ible contributor to portal pressure is the enhancedinflow of blood into the portal circulation caused bythe hyperdynamic state observed in cirrhotics and bygeneralized vasodilatation. Thus, an increase in portalpressure results from both an increase in resistance toportal flow and an increase in portal blood flow.

MAJOR SITES OF PORTOSYSTEMICANASTOMOSIS

In response to increased portal pressure, vesselsupstream dilate. Usually this causes no clinicalproblem. However, when varices form on the luminalside of the esophagus or stomach they are subject tobleeding. Other sites for clinically important varicesinclude the anorectal junction, anterior abdominalwall and retroperitoneum. These will not be furtherconsidered here. Physical factors such as the elasticproperties of the vessel and the intravariceal andintraluminal pressure are important determinants of

whether the varices will rupture. The main determi-nant of variceal rupture is the variceal wall tension,which is determined by La Place’s law. According tothe La Place law, the variceal wall tension (T) is basedon the transmural pressure (TP), the radius of thevessel (r) and the thickness of the vessel wall (w):4

T TpXr X w= [ ] −1

Since the varices are dilated, tortuous and thin-walledvessels they have an increased risk of rupture andbleeding. The Child–Pugh scoring system retains con-siderable value in defining the severity of liver diseaseand is highly relevant to the assessment of variceal riskin cirrhotics (Table 2). In cirrhotics varices develop atthe rate of 8% per year. Patients with small varicesdevelop large varices at the rate of 8% per year.5 Thisprogression correlates with the grade of cirrhosis suchas Child–Pugh class B or C, the presence of alcoholiccirrhosis, and the presence of red wale marks at thetime of baseline endoscopy.

In cirrhotics with varices, variceal hemorrhage occurs ata yearly rate of 5–15% per year. The most importantpredictors of the first variceal hemorrhage are: (i) Thesize of the varices; (ii) The presence and severity of redwale marks on endoscopy; and (iii) The degree of liver

Table 1. Causes of portal hypertension

Pre-sinusoidal Sinusoidal Post-sinusoidal

CommonSchistosomiasis

UncommonSarcoidosisCongenital hepatic fibrosisVinyl chlorideDrugsPortal vein thrombosis due to sepsis

CommonCirrhosis

UncommonCystic liver diseaseNodular regenerative diseaseMetastatic malignant disease

CommonRight heart failure

UncommonCostrictive pericarditisBudd–Chiari syndrome (extrahepatic)Veno-occlusive disease (intrahepatic)

Table 2. Child–Pugh score

1 2 3

Encephalopathy None Grade 1–2 (precipitant) Grade 3–4 (chronic)Ascites None Mild ModerateBilirubin (mg/dL) <2 2–3 >3Albumin (g/dL) >3.5 2.8–3.5 <2.8PT(sec prolonged) or INR <4 4–6 >6

<1.7 1.7–2.3 >2.3

Child–Pugh A: 5–6 points; Child–Pugh B: 7–9 points; Child–Pugh C: 10–15 points.INR, international normalized ratio; PT, prothrombin time.

Journal of Digestive Diseases 2011; 12; 25–3226 W Carey

© 2011 The AuthorJournal of Digestive Diseases © 2011 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to

Shanghai Jiaotong University School of Medicine and Blackwell Publishing Asia Pty Ltd.

dysfunction (i.e. higher Child–Pugh score). The inter-play between risk factors in the development of varicealhemorrhage is illuminated by a landmark prospectivemulticenter study that measured the 1-year probabilityof bleeding in cirrhotics with newly diagnosed variceswho received no preventive treatment (Table 3).6

MANAGEMENT OF ESOPHAGEAL VARICES

Since varices per se cause no symptoms, strategies todetect them are required. In brief, all cirrhotics shouldbe screened for the presence of esophageal varices atthe time of diagnosis and at intervals afterwards.Those with severe liver impairment and endoscopicstigmata such as red wale signs should undergo yearlysurveillance. Endoscopy remains the most reliableway of detecting varices and affords the possibility ofmanagement at the time of diagnosis. Newer tech-niques for looking at the esophageal varices such astrans-nasal endoscopy and capsule endoscopy mayhave a future role. The availability of liver stiffnesseither by ultrasound or magnetic resonance imagingtechnology holds promise in excluding a significantnumber of cirrhotics from the need for endoscopy, aslow liver stiffness correlates quite well with hepaticvenous pressure gradient (HVPG) < 10 mm Hg.7

MANAGEMENT OF ESOPHAGEAL VARICES

Prevention

To date primary prevention of varices in cirrhoticsremains elusive. Limited evidence fails to demonstratea role for beta blocker therapy in preventing the for-mation of esophageal varices in cirrhotics.8 Otherinnovative strategies remain to be developed.

Primary prophylaxis of esophagealvariceal bleeding

Primary prophylaxis of esophageal varices refers tomeasures taken for the prevention of first variceal

hemorrhage. The use of preventive strategies like betablockers and endoscopic variceal ligation (EVL) hasmarkedly decreased the rates of first variceal hemor-rhage. We and others have recently demonstrated theclinical effectiveness of screening and preventive strat-egies in the reduction of bleeding risk in cirrhotics.9

Non-selective b blockers such as propranolol ornadolol reduce portal venous pressure.10,11 They do soby the combined effect of b blocker which reduces thecardiac output and, more importantly, the effect of b2blocker, which causes splanchnic vasoconstrictionand thus results in a decrease in the portal venousflow. A decrease in HVPG – the difference between the‘free’ and ‘occluded’ pressure – reduces bleeding risk. AHVPG < 12 mm Hg essentially eliminates the risk ofhemorrhage and improves survival.12 Typical startingdoses are propranolol 20 mg b.i.d. or nadolol 40 mgonce daily. Titration aimed at achieving dosages toreduce the pulse rate by 25% from the baseline, main-taining a resting heart rate of 55–60 beats per minute,is recommended. The most common side effects ofb blockers include light-headedness, fatigue, coldextremities, bronchoconstriction and impotence.Caution in their use is advised in those with asthma,insulin dependent diabetes and peripheral vasculardisease. The risk of bleeding recurs when treatmentwith beta blockers is stopped and so prophylactictherapy is recommended indefinitely. Limited data areavailable for a range of other drugs. Carvedilol mayreduce portal pressure more than propranolol. Arecent randomized controlled trial of carvedilol atdoses of 6.25 to 12.5 mg/day indicated the superiorityof this agent compared to EVL. Until additionalstudies are available, carvedilol is not considered afirst-line therapy in variceal bleeding prophylaxis.13

The aim of EVL is to eradicate varices. Ligation haslargely supplanted injection sclerotherapy because it issafer. Most studies have shown either that EVL is eitherequivalent to or superior to beta blocker therapy in

Table 3. Risk of first hemorrhage in cirrhotics with esophageal varices6 1-year probability (%) of bleeding according to thesize, red wale markings and Child–Pugh class A, B and C

Child–Pugh A Child–Pugh B Child–Pugh C

S M L S M L S M L

Red wale markingsAbsent 6 10 15 10 16 26 20 30 42Mild 8 2 19 15 23 33 28 38 54Moderate 12 16 24 20 30 42 36 48 64Severe 16 23 34 28 40 52 44 60 76

L, large, M, medium, S, small.

Journal of Digestive Diseases 2011; 12; 25–32 Portal hypertension 27

© 2011 The AuthorJournal of Digestive Diseases © 2011 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated toShanghai Jiaotong University School of Medicine and Blackwell Publishing Asia Pty Ltd.

preventing first bleeding episodes. However, the smallrisk of inducing major variceal hemorrhage as a com-plication of banding has made some cautious aboutits use in this context. Additional limitations of EVLinclude the need for the endoscopic expertise and theneed for regular surveillance.

Reduction of portal pressure by surgically or radiologi-cally placed shunts has been studied as a means ofprimary bleeding prophylaxis but is not recom-mended. Compared to conventional treatment, surgi-cal shunts are associated with higher mortality, andTIPS with excess hepatic encephalopathy.

Active intervention to reduce bleeding likelihoodshould be directed to patients with varices withheightened risk for bleeding. These include all patientswith medium sized or large varices and all varices withstigmata (red color signs), indicating higher bleedingrisk, and in patients with Childs–Pugh B or C cirrho-sis. Beta blockers or EVL may be used.

Management of active esophagealvariceal bleeding

Vasoactive therapy

Active variceal bleeding is an emergency that requiresprompt attention with cautious intravascular volumesupport and blood transfusion, vasoactive therapy,antibiotics and endoscopy. Elements of the manage-ment of acute upper gastrointestinal bleeding include;(i) prompt patient resuscitation and stabilization;(ii) assessment of the onset and severity of bleeding;(iii) regional localization of the bleeding site; and(iv) control of the active bleeding episode.

For initial resuscitation a large bore peripheral i.v.access must be obtained. The patient should be evalu-ated for orthostatic changes in the blood pressure thatindicate significant blood loss. Blood should be typedand cross-matched and the hemoglobin, hematocrit,the platelet count and the prothrombin time shouldbe checked.

An infusion of crystalloid and colloid solution shouldbe started to restore the blood pressure and urineoutput to normal values. Blood volume expansionshould be undertaken promptly with the goal ofmaintaining hemodynamic stability and hematocritto a value not higher than 25%. Caution is advised toavoid over-transfusion with volume overload, whichincreases the risk of rebound portal hypertension and

induction of rebleeding.11 A transfusion of freshfrozen plasma and platelets can be considered inpatients with significant coagulopathy or thrombocy-topenia, or both.

Urgent intubation may be required prior to endoscopyto prevent aspiration, particularly in patients withhepatic encephalopathy. The patient should be con-tinually monitored for changes in blood pressure andheart rate.

Pharmacologic therapy with vasoconstrictors such assomatostatin (or its analogue, octreotide) should beundertaken whenever variceal hemorrhage is sus-pected, even before endoscopic verification. Oct-reotide causes vasoconstriction at pharmacologicaldoses and is the agent of choice in the US whereterlipressin is not currently approved by the Food andDrug Administration. It has the advantage of beingdevoid of serious side effects and requires no moni-toring. A 50-mg bolus should be followed by continu-ous i.v. infusion of 50 mg/hour, which should be usedas a 2–5-day course. Vapreotide in the same dose asoctreotide may also be considered.

Terlipressin is a synthetic analogue of vasopressin andis preferred to its parent compound, vasopressin,because it has a longer biological activity and fewerside effects. Both may produce intensive vasoconstric-tion and consequent ischemia and necrosis and needto be used with caution in a monitored environment(e.g. an intensive care unit). Terlipressin alone amongthe pharmacological agents used in the initial controlof variceal hemorrhage has been shown in somestudies both to control bleeding and improve survival.

Antibiotic therapy

Short-term antibiotic therapy in acute variceal hemor-rhage has been shown to decrease the rate of bacterialinfections, reduce rebleeding and improve sur-vival.14,15 All patients with cirrhosis who present withvariceal hemorrhage should be given antibiotics.Commonly used antibiotics are quinolones such asofloxacin, norfloxacin, ciprofloxacin and cephalospor-ins. Antibiotic schedules that can be used in the pro-phylaxis of bacterial infections in cirrhotic patientswith gastrointestinal hemorrhage are indicated inTable 4.

Once hemodynamic stability is achieved, an endos-copy is performed to ascertain the cause of bleeding




and to treat esophageal varices when they are thecause. EVL is most often used. EVL is done by suction-ing the varix into the suction channel of the endo-scope and applying a rubber band around the base.Multiple bands may be applied in a single session.Such therapy stops variceal bleed in about 80% ofcases and is repeated every month until the varices areobliterated. A regular follow up at 6–12-month inter-vals is recommended. EVL is more effective than thedirect injection of varices with sclerosing agents and isassociated with a lesser incidence of esophageal per-foration and rebleeding.5 Sclerotherapy may be per-formed in patients when EVL is not technicallyfeasible.

In dire situations active bleeding at endoscopy canmake endoscopic therapy difficult. In such cases anesophageal balloon tamponade can be used. Manyspecially designed tubes are available. Such therapy isassociated with a very high rebleeding rate once theballoon is deflated. Moreover, complications are fre-quent and include aspiration and esophageal perfora-tion. Balloon tamponade is most often used as abridge either to endoscopic or radiological control byTIPS.

TIPS is a radiological procedure in which a stent isplaced via the internal jugular vein between the portalvein and the hepatic vein to decrease the portal pres-sure. No method of controlling bleeding from eitheresophageal or gastric variceal hemorrhage has beenshown to be more effective in controlling bleedingand preventing subsequent bleeding episodes. Thetwo major drawbacks of the TIPS procedure are that itshigh technology character limits its availability, andthat the shunt has a propensity to result in hepaticencephalopathy. TIPS is clearly warranted when acutevariceal hemorrhage is not controlled with pharmaco-logical and endoscopic means. An expanded role forTIPS is discussed below.

SECONDARY PROPHYLAXIS OF ESOPHAGEALVARICEAL BLEEDING

Secondary prophylaxis refers to interventions aimed atreducing the likelihood and prevention of subsequentbleeds after an index bleed has occurred. Rebleedingrisk is greatest during the first 6 weeks following theindex bleed. This risk declines gradually and at about6 months after the bleed the risk is the same as forpatients with cirrhosis who have not had a bleed.16

Interventions include one or more of the following:the endoscopic obliteration of the varices; the phar-macological reduction of portal pressure and theradiological placement of the stents to reduce portalpressure. Liver transplantation may be an option if thepatient’s hepatic function is sufficiently impaired toqualify for transplantation services.

Beta blocker treatment and EVL remain the two mostcommon ways of reducing risk of second bleeds.Compared to no treatment, each is superior. Com-pared to each other, EVL is most often either equiva-lent to or superior to beta blockers in preventingbleeding, although a few studies suggest that betablockers are superior. One study confirms the superi-ority of EVL in producing lower rebleeding rates butsuggests a survival advantage of beta blocker (plusisosorbide mononitrate), presumably by mechanismsindependent of bleeding.17

If EVL and beta blockers are effective in preventingrebleeding, both together might represent the beststrategy. A meta-analysis of randomized trials compar-ing endoscopic therapy plus beta blockade with eithertherapy alone has recently been published.18 Table 5outlines the study design and key findings of thestudies making up this meta-analysis. An importantlimitation of this meta-analysis is that the endoscopictherapy used in most of the studies was injectionsclerotherapy rather than band ligation. Practice

Table 4. Selected study regimens establishing benefits of antibiotics in acute variceal hemorrhage

Antibiotic Dose Route Duration (days)

Norfloxacin 400 mg b.i.d. Per oral or NG tube 7Ofloxacin 400 mg b.i.d. I.v. then per oral 10Ciprofloxacin + amoxiclav 200 mg b.i.d.

1 gm/200 mg b.i.d.I.v. then per oral (1 day after

bleeding stopped)3, after bleeding

stoppedCiprofloxacin 500 mg b.i.d. Per oral 7Norfloxacin 400 mg b.i.d. Per oral 7Ofloxacin 200 mg b.i.d. I.v. then per oral (at the 3rd day) 7Ceftriaxone 1 gm daily I.v. 7

NG, nasogsatric.



guidelines recommendations call either for betablocker therapy (with or without vasodilators such asnitroglycerin), or repeated endoscopic band ligation(often with beta blockers, at least until the varices areobliterated). Indeed, there is evidence supportingeach approach. The controversy continues regardingoptimal secondary bleeding prophylaxis. A recent ran-domized controlled trial indicates that EVL added nobenefit to beta blockade alone in secondary bleedingprophylaxis.19

TIPS and portosystemic shunts reduce rebleeding butat the expense of a significantly increased risk ofhepatic encephalopathy. The surgical creation ofshunts has been largely abandoned in favor of TIPS,despite the demonstration that these modalities areequivalent in efficacy, survival, incidence of portosys-temic encephalopathy and cost.20 A recent multicen-tered randomized clinical trial restricted to patientsshowed a rebleeding rate of 5.5% over 5 years if thosewho received a distal splenorenal shunt, comparedwith 10.5% in those who received TIPS.

As mentioned, concerns about encephalopathy have,until now, relegated TIPS to a secondary role in themanagement of esophageal varices. A landmark ran-domized controlled trial took a fresh look at the appli-cability of early TIPS in those with advanced liverdisease (Child–Pugh > 6 < 14) who suffered a varicealbleed.21 In this study, all patients received endoscopictreatment, vasoactive therapy and antibiotics. Thepatients were randomized within 24 h of a varicealhemorrhage to receive either a TIPS (using apolytetrafluoroethylene-covered stent) or continua-tion of vasoactive therapy, followed after 3–5 days by

long-term treatment with beta blocker and long-termendoscopic band ligation (the current standard ofcare). During the follow-up period those randomizedto early TIPS had a much lower bleeding rate(P < 0.001) and a better survival rate (P = 0.01). The1-year likelihood of freedom from bleeding was 97%and 50%, respectively. Actuarial 1-year survival was81% in the early TIPS group and 61% in the conven-tionally treated group (P < 0.001). No significant dif-ferences were seen in the incidence of hepaticencephalopathy.

My recommendations for secondary bleeding prophy-laxis are as follows: patients who have bled fromesophageal varices warrant intervention to reducethe risk of rebleeding. For those with a Child–Pughscore of 5–6, a combination of EVL and betablocker therapy appears the best choice. When theChild–Pugh score is 7–13, early placement of apolytetrafluoroethylene-covered stent is preferred. Forthose with higher Child–Pugh scores, EVL is recom-mended. Appropriate patients should be referred forliver transplantation services.

GASTRIC VARICES

Gastric varices are classified according to their rela-tionship with esophageal varices and their location inthe stomach:

1. Gastroesophageal varices (GOV) are an extensionof esophageal varices. They are divided intoGOV1, which are continuous with the esophagealvarices along the lesser curvature and GOV2,which are along the fundus.

Table 5. Strategies comparing single versus dual modality for risk of reduction of rebleeding from esophageal varices

Endoscopy alone versusendoscopic + pharmacotherapy

N = 18 studies

Pharmacotherapy alone versusendoscopy + pharmacotherapy

N = 5 studies

1 year rebleed Actuarial mortality 1 year rebleed Actuarial mortalityEndoscopy (%) 37 17Endoscopy +

pharmacotherapy (%)25* 14 37* 26

Pharmacotherapy alone(%)

53 33

Relative risk or OR 0.68 0.78 0.71 0.7095% CI 0.52–0.89 0.58–1.07 0.59–0.86 0.46–1.06

P = 0.85 P = 0.22Comments Endoscopic variceal ligation (EVL) in 3/18

studies; sclerotherapy often weeklyLigation (EVL) in 2/5 studies; often daily for

10–21 days

*P < 0.05.




2. Isolated gastric varices (IGV) occur in the absenceof esophageal varices. IGV1 are located in thefundus and tend to be tortuous and complex andIGV2 are located in the body, antrum or aroundthe pylorus. The presence of IGV1 indicates thepossible presence of splenic vein thrombosis.

MANAGEMENT OF GASTRIC VARICES

Acute bleeding from gastric varices

Bleeding from gastric varices is typically high volumein nature and can present with massive hematemesis.In patients who bleed from gastric fundal varicesendoscopic variceal obturation with tissue adhe-sives such as N-butyl-cyanoacrylate, isobutyl-2-cyanoacrylate or thrombin is preferred as it isassociated with better control of the initial hemor-rhage as well as lower rates of rebleeding.22 Howeversince this therapy is associated with bacteremia, anantibiotic prophylaxis should be considered in high-risk patients who have advanced liver disease andsevere hemorrhage.23 TIPS can be considered inpatients after the failure of one endoscopic therapeuticsession or in patients with gastric varices who experi-ence an early rebleed.

SECONDARY PROPHYLAXIS OFGASTRIC VARICES

Patients who have recovered from an initial bleedhave a very high risk of rebleeding and death so thesepatients should be started on therapy to prevent recur-rence. Non-selective beta blockers, nitrates and TIPS,and shunt surgery can be used for the secondary pro-phylaxis of gastric varices. Non-selective beta blockerscan be used alone or in combination with nitrates butthe combination is associated with a greater incidenceof side effects. There are insufficient data to recom-mend endoscopic therapy for gastric varices. TIPS canbe considered in patients who experience recurrentvariceal hemorrhage. Shunt surgery can be done wherethe expertise is available as it is associated with a lesserincidence of hepatic encephalopathy. Liver transplan-tation is the last option if all these therapies fail.

Portal hypertensive gastropathy

Approximately 30–50% of the bleeding episodes inpatients with portal hypertension originate from anon-variceal source. Most of this non-variceal bleed-ing is due to portal hypertensive gastropathy. This isseen as punctate erythema on endoscopy. Indolent

minor bleeding from these erythematous patches mayoccur, causing iron deficiency anemia.

Treatment is directed towards controlling thesymptom, which is mainly iron deficiency anemia. Ifthere is severe and continuous bleeding local therapiessuch as argon photocoagulation or other mucosalablative techniques can be used. TIPS may reducebleeding from portal hypertensive gastropathy.Another gastric mucosal lesion with bleeding poten-tial associated with portal hypertension is gastricantral vascular ectasia. These lesions do not respond aswell as portal hypertensive gastropathy to TIPS and areusually treated with argon photocoagulation.

REFERENCES

1 Groszmann RJ, Abraldes JG. Portal hypertension: frombedside to bench. J Clin Gastroenterol 2005; 39 (Suppl 2):S125–30.

2 Carbonell N, Pauwels A, Serfaty L et al. Improved survivalafter variceal bleeding in patients with cirrhosis over thepast two decades. Hepatology 2004; 40: 652–9.

3 Hobolth L, Krag A, Bendtsen F. The recent reduction inmortality from bleeding oesophageal varices is primarilyobserved from days 1 to 5. Liver Int 2010; 455–62.

4 Sharara AI, Rockey DC. Gastroesophageal varicealhemorrhage. N Engl J Med 2001; 345: 669–81.

5 Garcia-Pagan JC, Bosch J. Endoscopic band ligation inthe treatment of portal hypertension. Nat Clin PractGastroenterol Hepatol 2005; 2: 526–35.

6 North Italian Endoscopic Club for the Study and Treatmentof Esophageal Varices. Prediction of the first varicealhemorrhage in patients with cirrhosis of the liver andesophageal varices. A prospective multicenter study. N Engl JMed 1988; 319: 983–9.

7 Vizzutti F, Arena U, Romanelli RG et al. Liver stiffnessmeasurements predicts severe portal hypertension inHCV-related cirrhosis. Hepatology 2007; 45: 1290–7.

8 Groszmann RJ, Garcia-Tsao G, Bosch J et al. Beta-blockers toprevent gastroesophageal varices in patients with cirrhosis.N Engl J Med 2005; 353: 2254–61.

9 Moodley J, Lopez R, Carey W. Compliance with practiceguidelines and risk of a first esophageal variceal hemorrhagein patients with cirrhosis. Clin Gastroenterol Hepatol 2010;703–8.

10 Hayes PC, Davis JM, Lewis JA et al. Meta-analysis of thevalue of propranolol in prevention of variceal hemorrhage.Lancet 1990; 336: 8708.

11 D’Amico G, Pagliaro L, Bosch J. Pharmacological treatmentof portal hypertension; an evidence based approach. SeminLiver Dis 1999; 19: 475–505.

12 Groszmann RJ, Bosch J, Grace N et al. Hemodynamic eventsin a prospective randomized trial of propranolol vs placeboin the prevention of the first variceal hemorrhage.Gastroenterology 1990; 99: 1401–7.

13 Tripathi D, Ferguson JW, Kochar N et al. Randomizedcontrolled trial of carvedilol versus variceal band ligationfor the prevention of first variceal bleed. Hepatology 2009;50: 825–33.

14 Bernard B, Grange JD, Khac EN et al. Antibiotic prophylaxisfor the prevention of bacterial infections in cirrhotic



patients with gastrointestinal bleeding: a meta-analysis.Hepatology 1999; 29: 1655–61.

15 Soares-Weise K, Brezis M, Tur-Kaspa R, Leibovici L.Antibiotic prophylaxis for cirrhotic patients withgastrointestinal bleeding (Cochrane Review). CochraneDatabase Syst Rev 2002; 2: CD002907.

16 Graham DY, Smith JL. The course of patients after varicealhemorrhage. Gastroenterology 1981; 80: 800–9.

17 Lo GH, Chen WC, Lin CK et al. Improved survival inpatients receiving medical therapy as compared withbanding ligation for the prevention of esophageal varicealrebleeding. Hepatology 2008; 48: 580–7.

18 Gonzalez R, Zamora J, Gomez-Camarero J et al.Meta-analysis: combination endoscopic and drug therapy toprevent variceal re-bleeding in cirrhosis. Ann Intern Med2008; 149: 109–22.

19 García-Pagán JC, Villanueva C, Albillos A, Bañares R et al.Nadolol plus isosorbide mononitrate alone or associated

with band ligation in the prevention of recurrent bleeding: amulticentre randomised controlled trial. Gut 2009; 58:1144–50.

20 Henderson JM, Boyer TD, Kutner MH et al. Distalsplenorenal shunt versus transjugular intrahepatic portalsystematic shunt for variceal bleeding: a randomized trial.Gastroenterology 2006; 130: 1643–51.

21 García-Pagán JC, Cac K, Bureau C et al. Early use of TIPS inpatients with cirrhosis and variceal bleeding. N Engl J Med2010; 362: 2370–9.

22 Lo GH, Lai KH, Cheng JS et al. A randomised trial of butylcyanoacrylate injection versus band ligation in themanagement of bleeding gastric varices. Hepatology 2001;33: 1060–4.

23 Chen WC, Hou MC, Lin HC et al. Bacteremia afterendoscopic injection of N-butyl-2-cyanoacrylate for thegastric variceal bleeding. Gastrointest Endosc 2001; 54:214–8.




portal hypertension: diagnosis and management with particular reference to variceal hemorrhage

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