Best Practice & Research Clinical Gastroenterology 27 (2013) 649664

Contents lists available at ScienceDirect

Best Practice & Research Clinical

Gastroenterology

Variceal and other portal hypertension related

bleeding
Fanny Turon, MD, Clinical Research Fellow a,
Stefania Casu, MD, Internal Medicine Resident a,
Virginia Hernndez-Gea, MD, PhD, Specialist in
Hepatology a, b, Juan Carlos Garcia-Pagn, MD, PhD, Head of
Hepatic Hemodynamic Unit a, b, *
a

Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Institut de Malalties Digestives i Metaboliques,

Hospital Clinic, Institut de Investigacions Biomdiques August Pi i Sunyer (IDIBAPS), University of Barcelona,
Barcelona, Spain
b Centro de Investigacin Biomdica en Red de Enfermedades Hepticas y Digestivas (CIBERehd), Spain

abstract
Keywords:
Endoscopic band ligation
Gastric varices
TIPS
BRTO
Portal hypertensive gastropathy
GAVE

Variceal bleeding is one of the commonest and most severe complications of liver cirrhosis. Even with the current best medical care,
mortality from variceal bleeding is still around 20%. When cirrhosis is
diagnosed, varices are present in about 3040% of compensated patients and in 60% of those who present with ascites. Once varices have
been diagnosed, the overall incidence of variceal bleeding is in the
order of 25% at two years. Variceal size is the most useful predictor for
variceal bleeding, other predictors are severity of liver dysfunction
(ChildPugh classication) and the presence of red wale marks on the
variceal wall. The current consensus is that every cirrhotic patient
should be endoscopically screened for varices at the time of diagnosis
to detect those requiring prophylactic treatment. Non-selective betaadrenergic blockers (NSBB) and endoscopic band ligation (EBL) have
been shown effective in the prevention of rst variceal bleeding. The
current recommendation for treating acute variceal bleeding is to
start vasoactive drug therapy early (ideally during the transferral or to
arrival to hospital, even if active bleeding is only suspected) and
performing EBL. Once bleeding is controlled, combination therapy
with NSBB EBL should be used to prevent rebleeding. In patients at
high risk of treatment failure despite of using this approach, an early

* Corresponding author. Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clnic, Villaroel 170, Barcelona 08036, Spain.
Fax: 34 932279856.
E-mail address: jcgarcia@clinic.ub.es (J.C. Garcia-Pagn).
1521-6918/$ see front matter 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bpg.2013.08.004

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covered-TIPS within 72 h (ideally 24 h) should be considered. Data on

management of gastric variceal bleeding is limited. No clear recommendation for primary prophylaxis can be done. In acute cardiofundal variceal bleeding, vasoactive agents together with
cyanoacrylate (CA) injection seem to be the treatment of choice.
Further CA injections and/or NSBB may be used to prevent rebleeding.
TIPS or Balloon-occluded retrograde transvenous obliteration when
TIPS is contraindicated may be used as a rescue therapy.
2013 Elsevier Ltd. All rights reserved.

Introduction
Variceal bleeding is one of the commonest and most severe complications of liver cirrhosis. Even
with the current best medical care, mortality from variceal bleeding is still around 20%. Moreover,
variceal bleeding often leads to deterioration in liver function, and it is a common trigger for other
complications of cirrhosis, such as bacterial infections or hepatorenal syndrome.
Natural history of varices in cirrhosis
When cirrhosis is diagnosed, varices are present in about 3040% of compensated patients and in
60% of those who present with ascites [1]. The annual incidence of new varices in those cirrhotic
patients who present without is about 510% [2]. A hepatic venous pressure gradient (HVPG) over
10 mmHg is the strongest predictor for the development of varices [3].
Once developed, the reported rate of progression from small to large varices is highly variable,
ranging from 5% to 30% per year [2]. The factor that has been most consistently associated with variceal
progression is baseline ChildPugh or its worsening during follow-up [2,4]. Other factors were alcoholic etiology of cirrhosis and the presence of red wale markings [2]. It has been shown that when
HVPG decreases below 12 mmHg (either spontaneous or caused by drug therapy or TIPS) esophageal
varices decrease in size [5]. Thus, an increased HVPG plays a key role both in development and progression of the varices.
Once varices have been diagnosed, the overall incidence of variceal bleeding is in the order of 25% at two
years [6]. Variceal size is the most useful predictor for variceal bleeding [7], other predictors are severity of
liver dysfunction (ChildPugh classication) and the presence of red wale marks on the variceal wall [8].
These risk indicators have been combined in the NIEC index which allows to classify patients in different
groups with predicted one-year bleeding risk ranging from 6% to 76% [8]. The risk of bleeding is very low
(between 1 and 2%) in patients without varices at the rst examination, and increases to about 5% per year
in those with small varices and to 15% per year if medium or large varices are present at diagnosis [1].
Prevention of rst bleeding from esophageal varices
Screening for esophageal varices
The current consensus is that every cirrhotic patient should be endoscopically screened for varices
at the time of diagnosis [9] to detect those requiring prophylactic treatment. In patients without varices
on initial endoscopy, a second (follow-up) evaluation should be performed after 23 years [10]. In
patients with small varices, if beta-blockers are not initiated, a follow-up endoscopy should be performed every 12 years to check for a possible increase in size, based on an expected 10%15% per year
rate of progression of small to large varices. This time must be shortened in case of clinical decompensation. No follow-up endoscopy is needed once beta-blockers are started.
Doppler-US [11] or transient elastography measurements by broscan [1214] have been proposed
as possible surrogate markers of the presence of esophageal varices but none has proved to be accurate
enough to safely avoid endoscopy.

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Selection of patients for prophylaxis

Medium to large varices are considered high risk varices subsidiary for prophylactic treatment.
However, it is well established that small varices with red signs on its wall or ChildPugh class C patients have a bleeding risk that is similar to that of large varices [8]. In addition, it has been suggested
that beta-adrenergic blockers may reduce the rate of progression from small to large varices, and
decrease the incidence of variceal bleeding in patients with small varices [9]. Thus, current guidelines
recommend initiating beta-blockers in patients with medium to large varices, but also in patients with
small varices that had red signs or if the patient belong to the ChildPugh C class [10].
There is no effective treatment to prevent the development of varices [15].
Treatment for the prevention of rst bleeding: beta-adrenergic blockers vs endoscopic band ligation
Non-selective beta-adrenergic blockers (NSBB) (propranolol or nadolol) have been proven effective
in the prevention of variceal bleeding (from 24% to 15% after a median follow-up 2 years) and almost
signicantly reduce mortality (from 27% to 23%) [6].
Therapy with beta-adrenergic blockers should be maintained indenitely, since when these are withdrawn the risk of variceal hemorrhage returns to what would be expected in an untreated population [16].
The addition of isosorbide 5-mononitrate (ISMN) increases the HVPG reduction of beta-adrenergic
blockers [17]. However, it is less clear whether this translates into a greater clinical efcacy in primary
prophylaxis. An open trial showed a lower rate of rst bleeding in patients receiving nadolol ISMN
than in those receiving nadolol alone [18,19]. However, a large, randomized, double-blind study failed
to conrm these results [20]. Currently, in primary prophylaxis it is not recommended this combination, neither ISMN administered alone.
However, circa 25% of cirrhotic patients with high risk esophageal varices may have either contraindications or cannot tolerate beta-adrenergic blockers.
Endoscopic band ligation (EBL) is effective in preventing the rst variceal bleeding in patients with
medium to large varices [21]. There is no agreement on how frequently varices should be ligated, the
interval varying from every 1 to every 4 weeks. One trial evaluated the effectiveness and complications
of EBL every two weeks vs every two months concluded that the two-month interval scheme obtained
a higher total eradication rate and lower recurrence rate [22]. Thus, although admittedly weak, current
evidence favors at least monthly intervals. Once the varices are eradicated, follow-up endoscopies
should be performed at 13 months and every 6 months thereafter, and varices should be reeradicated upon recurrence.
So far different trials have compared EBL with beta-blockers for the primary prevention of variceal
bleeding. The meta-analysis of these trials shows an advantage of EBL over beta-adrenergic blockers in
terms of prevention of rst bleeding, without differences in mortality [23]. These results, however,
deserve several comments. Firstly, most trials were underpowered or lacked any sample size calculation. Moreover, four trials were prematurely stopped [2427], three of them due to futility. When
restricting the meta-analysis to trials fully published with more than 100 patients no differences between beta-blockers and EBL were found [28]. Thus, available evidence to favor EBL over beta-blockers
is very weak.
Another important issue when comparing two different treatment alternatives is the incidence of
adverse events. Most side effects related to beta-blockers (hypotension, tiredness, breathlessness,
impotence, insomnia) are easily managed by adjusting the dose or discontinuing the drug and do not
require hospital admission [29], while side effects related to EBL, mostly bleeding episodes related to
the procedure, frequently required hospitalization, blood transfusion and even might lead to the death
of the patient.
According with this results, beta-blockers are recommended as rst choice in Child A patients with
medium/large varices and no red signs, and either beta-blockers or EBL can be used as rst choice in
patients with higher risk varices [10,30]. The choice of treatment should be based on local resources
and expertise, patient preference and characteristics, side effects and contra-indications [10].
Carvedilol is a non-selective beta-blocker with an intrinsic alpha adrenergic blocker effect that
produces a greater decrease in portal pressure than propranolol [31], Recently, one study compared EBL

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against carvedilol in primary prolaxis showing that carvedilol signicantly reduced the incidence of
variceal bleeding as compared to EBL [32]. Another study conrms that the greater reduction in HVPG
caused by carvedilol vs propranolol (19% vs 12%) and that carvedilol can achieve hemodynamic
response (decrease HVPG by more than 20% or below 120 mmHg) in a signicant group of patients
nonresponders to propranolol (up to 72% of hemodynamic response vs 39% using only propranolol).
Responders to propranolol or carvedilol had a lower risk of rst bleeding and clinical decompensation
than nonresponders that were treated with EBL [33].
The actual role of carvedilol in primary prophylaxis still needs to be further evaluated but it may be a
good alternative in patients with cirrhosis and arterial hypertension because it may produce a greater
reduction in mean arterial pressure (MAP) than propranolol.
Prevention of recurrent bleeding from esophageal varices
Patients surviving a rst episode of variceal bleeding have a very high risk of rebleeding and death,
then, prevention of recurrent bleeding is mandatory [10].
The meta-analysis of four available trials have shown a similar efcacy preventing rebleeding and in
survival in patients receiving optimal endoscopic treatment (EBL) or optimized pharmacological
treatment (combination of betablockers and ISMN) [3437]. A recent meta-analysis suggests that the
combination of drug therapy with EBL is probably the best strategy for preventing variceal rebleeding
[38]. However, data evaluating this issue are not very strong. Indeed, two trials have shown that the
association of beta-adrenergic blockers and endoscopic band ligation fares better than band ligation
alone [39,40]. A benecial effect was not conrmed in a third study [41]. In addition, another two trials
failed to show a clear-cut benet from adding EBL to combined pharmacological therapy with
nadolol IMN [42,43]. In the absence of more studies, current guidelines recommend combination
therapy (drugs EBL) for preventing rebleeding [10,30].
TIPS in the prevention of rebleeding
TIPS has proven better than the combination of ISMN and propranolol [44], and to endoscopic
therapy in the prevention of variceal rebleeding [45], with rebleeding rates of 923%. However, the
high effectiveness in preventing recurrent bleeding is associated with an increased risk of encephalopathy, without a survival benet. Because of this, TIPS is currently recommended as rescue therapy
for patients who fail endoscopic and pharmacological treatment for the prevention of re-bleeding [10].
In this indication, uncovered bare TIPS has been compared with surgical shunts in two RCTs (8 mm
portocaval H-graft shunt in one, and distal splenorenal shunt (DSRS) in the other) [46,47]. The rst
study showed a signicantly lower rebleeding rate in the shunt group without differences in survival.
However, no differences in these parameters were observed in a second and larger trial, although at an
expenses of a higher reintervention rate in the TIPS group (82%) [47]. However, the obstruction and
reintervention rates are markedly decreased with the use of polytetrauoroethylene (PTFE)-covered
stents [48]. According to these data, TIPS using PTFE-covered stents represents the rescue therapy of
choice for failures of medical and endoscopic treatment.
The acute bleeding episode
Ruptured esophageal varices is the cause of 70% of all upper gastrointestinal bleeding episodes in
patients with portal hypertension [49]. Diagnosis is established at emergency endoscopy based on
observing one of the following: a) active bleeding from a varix (observation of blood spurting or oozing
from the varix); b) white nipple or clot adherent to a varix; c) presence of varices without other potential sources of bleeding. Current guidelines recommend to perform endoscopy within 12 h after
admission, specially in patients with hematemesis or hemodynamic instability.
General management of the bleeding episode includes correcting hypovolemia and at preventing
complications associated with gastrointestinal bleeding (bacterial infections, hepatic decompensation,
renal failure), which are independent of the cause of the hemorrhage (Fig. 1). Initial resuscitation
should be aimed at restoring an appropriate delivery of oxygen to the tissues. Airway should be

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653

Fig. 1. Proposed algorithm for management of esophageal variceal bleeding.

immediately secured, especially in encephalopatic patients, since the patient is at risk of bronchial
aspiration of gastric content and blood. This risk is further exacerbated by endoscopic procedures.
Endothracheal intubation is mandatory if there is any concern about the safety of the airway.
Blood volume replacement should be initiated as soon as possible with plasma expanders, aiming at
maintaining systolic blood pressure around 100 mmHg. Avoiding prolonged hypotension is particularly
important to prevent infection and renal failure, which are associated with increased risk of rebleeding
and death [50]. Overtransfusion should be avoided, not only because of the risks inherent with blood
transfusion, but also because a restrictive strategy aimed to maintain the hemoglobin level between 7
and 8 g/dl signicantly improved outcomes in patients with acute upper gastrointestinal bleeding [51]
except in patients with rapid ongoing bleeding or with underlying ischemic heart disease. Despite a
promising initial study [52], there is no indication for the use of rVIIa in the treatment of acute variceal
bleeding [53].
Infection is a strong prognostic indicator in acute variceal bleeding [54]. The use of prophylactic
antibiotics has been shown to reduce both the risk of rebleeding [55] and mortality [56]. Therefore,
antibiotics should be given to all patients from admission. Quinolones are frequently used (noroxacin
400 mg/bid) due to its easy administration and low cost [57]. However, in high risk patients (hypovolemic shock, ascites, jaundice, malnutrition) patients with previous quinolone prophylaxis or in
settings with quinolone-resistant bacteria i.v. ceftriaxone (1 g/day) must be used [58].
Variceal bleeding can trigger hepatic encephalopathy but there is no strong data to support the
prophylactic use of lactulose to prevent it [10].
Specic therapy for control of bleeding
Pharmacological therapy
The action of vasoactive drugs is to reduce variceal pressure by decreasing variceal blood ow. The
selection of the drug depends on the local resources. Recently a meta analysis explored the efcacy of
vasoactive medications in acute variceal bleeding, including 30 trials with a total of 3111 patients.
Although the quality of evidence in this meta analysis was very low, vasoactive agents were associated

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with lower 7-day mortality, improvement in hemostasis, lower transfusion requirements and shorter
duration of hospitalization, with no differences in efcacy in studies comparing the different vasoactive
agents [59].
Vasopressin was the rst drug used but was abandoned 25 years ago because of the severity of its
cardiovascular adverse events. The association of vasopressin infusion plus nitroglycerin resulted in
enhanced fall in portal pressure and less marked systemic effects, and has been shown to be more
effective and safer than vasopressin [6]. This combination is still used in countries were neither terlipressin nor somatostatin are available, but should not be maintained for more than 48 hours because
of an increased incidence of side-effects.
Terlipressin is a long-acting triglycyl lysine derivative of vasopressin. Clinical studies have consistently shown less frequent and severe side effects with terlipressin than with vasopressin, (even if
associated with nitroglycerin).
Terlipressin may be initiated as early as variceal bleeding is suspected at a dose of 2 mg/4 hours for
the rst 48 h, and it may be maintained for up to 5 days at a dose of 1 mg/4 hours to prevent rebleeding
[60]. The most common side-effect of this drug is abdominal pain. Serious side effects such as peripheral or myocardial ischemia occur in less than 3% of the patients [60]. The overall efcacy of terlipressin in controlling acute variceal bleeding at 48 hours is of 7580% across trials [61], and of 67% at
5-days [60].
Somatostatin is empirically used as an initial bolus of 250 mg followed by a 250 mg/h infusion that is
maintained until the achievement of a 24 h bleed-free period. The bolus injection can be repeated if
bleeding is uncontrolled. Therapy should be maintained for up to 5 days to prevent early rebleeding
[62]. Minor side-effects, such as nausea, vomiting and hyperglycemia occur in up 30% of patients Somatostatin has been shown to be equivalent to terlipressin and to endoscopic therapy in the control of
acute variceal bleeding, prevention of early rebleeding, mortality or in the incidence of adverse events
[6]. The use of higher doses of somatostatin (500 mg/h) causes a greater fall in HVPG and have been
suggested to increase the clinical efcacy in the subset of patients with active bleeding at emergency
endoscopy [63].
Octreotide is a somatostatin analog with longer half life. The optimal doses are not well determined.
It is usually given as an initial bolus of 50 mg, followed by an infusion of 25 or 50 mg/h. The efcacy of
octreotide as a single therapy for variceal bleeding is controversial. However, RCTs using octreotide
after sclerotherapy have shown a signicant benet in relation to sclerotherapy alone in terms of
reducing early rebleeding [64]. Mortality, however, was not affected [6,64]. These results suggest that
octreotide may improve the results of endoscopic therapy but has uncertain effects if used alone.
Endoscopic therapy
Both sclerotherapy and band ligation (EBL) have shown to be effective in the control of acute variceal bleeding. Meta-analysis shows that EBL is better than endoscopic injection sclerotherapy (EIS) in
the initial control of bleeding, and is associated with less adverse events and improved survival.
Additionally, EIS, but not EBL, may increase portal pressure [65]. Therefore EBL is the endoscopic
therapy of choice in acute variceal bleeding, though injection sclerotherapy is acceptable if band
ligation is not available or technically difcult. Endoscopic therapy can be performed at the time of
diagnostic endoscopy, early after admission, provided that a skilled endoscopist is available.
Current recommendations for initial treatment
The current recommendation is to start vasoactive drug therapy early (ideally during the transferral
or to arrival to hospital, even if active bleeding is only suspected) and performing EBL (or injection
sclerotherapy if band ligation is technically difcult) after initial resuscitation [10,30]. Current
recommendation is to maintain drug therapy for 25 days [10].
Rescue therapies: tamponade, surgery and TIPS
In 1020% of patients variceal bleeding is unresponsive to initial endoscopic and/or pharmacologic
treatment. If bleeding is mild and the patient is stable a second endoscopic therapy might be

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655

attempted. If this fails, or bleeding is severe, the patient should be offered a derivative treatment,
before his clinical status further deteriorates.
Both TIPS and surgical shunts are extremely effective controlling variceal bleeding. TIPS is rst
choice, since most patients requiring rescue treatment have advanced liver disease. In patients with
sepsis, inotropic support, ventilation after aspiration, and deterioration of liver and renal function
mortality after TIPS placement is nearly 100%. Anyhow, rarely, if ever, a patient with a ChildPugh score
over 13 will survive a rescue TIPS.
A recent trial has shown that the performance of an early TIPS with a PTFEcovered stent in patients
at high risk of treatment failure (dened as Child B with active bleeding or Child C up to 13 points) was
associated with signicant reduction in the failure to control bleeding and in rebleeding without an
increase in encephalopathy rates and improving survival in relation to the current standard of care
[66]. These results have been conrmed in an observational study performed in those centers
participating in the RCT once they adopted the early-TIPS strategy to treat high risk variceal bleeding.
Thus, in patients of high risk of treatment failure, an early TIPS within 72 h (ideally 24 h) should be
considered [10].
Balloon tamponade can be used as a temporal bridge (less than 24 h) until denite treatment is
instituted, it achieves hemostasis in 60%90% of variceal bleedings. Bleeding recurs after deation in
over half of the cases and severe complications are common. Recent data suggest that self-expanding
covered esophageal metal stent may be an alternative to the SengstakenBlakemore balloon in refractory esophageal variceal bleeding with the advantage of less severe complications despite longer
periods of treatment [67,68]. Nevertheless, further adequately designed trials are required.
Gastric varices
Gastric varices, developed in about 20% of patients with portal hypertension, are less prevalent than
esophageal varices and represent 510% of all upper digestive bleeding episodes in cirrhosis [23,69].
According to Sarin [70], gastric varices are classied on gastroesophageal varices (GOV) type 1 (GOV1),
the most frequently detected (about 75% of all gastric varices), that extend along the lesser curvature
and type 2 (GOV2) that extend from EV along the fundus. Isolated gastric varices (IGV) include IGV1
which are those located in the fundus of the stomach that are also called fundal varices and IGV2 which
refer to ectopic varices located anywhere in the stomach [70]. This classication is relevant because risk
of bleeding, treatment and outcome of these types of GV is different. However most of the current
studies dealing with GV management do not differentiate between GV subtypes. As for EV, the presence of red spots, gastric variceal size and ChildPugh class (C > B > A) are considered as risk factors for
hemorrhage [69]. GOV2 and IGV1, usually grouped as cardiofundal varices, may bleed at relatively low
HVPG (1012 mmHg) probably due to the fact that these varices are usually very large and therefore
their wall tension (which is determined as the product of transmural pressure and vessel radius) may
reach high values at a lower pressure compared to esophageal varices.
The one-year risk of GV bleeding has been reported to be around 1016% and tends to be more severe,
requiring often more transfusions, and having a higher mortality rate then esophageal varices [23,70].
Up to now, there are not enough data to establish formal recommendations about GVs primary prophylaxis. Although the efcacy has not been demonstrated, considering its low risk, NSBB can be used.
Treatment of gastric varices
The management of gastric varices still remains a therapeutic challenge because of the limited
number of clinical trials specically done in these patients [71]. General consensus is that the initial
management is similar to that of esophageal variceal bleeding, including the use of prophylactic antibiotics, a careful replacement of volemia with a restrictive transfusion policy, and the early administration of vasoactive drugs (Fig. 2).
Endoscopic therapy
Specic high quality data on the use of endoscopic therapy for acute GV bleeding is limited and in
most published RCT only half of patients included in the trials had cardiofundal varices. Despite these

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Fig. 2. Proposed algorithm for management of gastric variceal bleeding.

limitations, most uncontrolled series report a high rate of control of bleeding with the use of tissue
adhesives such as Cyanoacrylate (CA) (>90%) [72]. In addition, small size RCTs comparing tissue adhesives vs either EBL or EIS have shown that tissue adhesives are equally [73] or more [74,75] effective
in the control of acute bleeding and more effective than both in preventing rebleeding. GOV1 varices
are usually treated as esophageal varices with EBL, although some investigators also recommend the
use of tissues adhesives for GOV1 varices too [76]. On the other hand, endoscopic therapy with tissue
adhesives, mainly CA, is the recommended therapy for acute bleeding from IGV1 and GOV2 [10]. Band
ligation for small GOV2 varices may be used if obliteration with tissue adhesives is not available [30].
EIS is ineffective for the treatment of the isolated gastric varices [71,77].
Rebleeding rates after an acute GV bleeding episode treated with tissue adhesives (mainly CA) range
from 7% to 65% with most of the large series reporting rates below 15%. Thus, after initial hemostasis with
tissue adhesives, repeated sessions are usually performed on a 2 to 4-weekly basis until endoscopic
obliteration is achieved. Several case-series and controlled studies have specically evaluated the effect of
long term injections of tissue adhesives (mainly CA) in order to prevent GV rebleeding. In most of these
studies eradication is achieved with 24 injections with a volume ranging from 1 to 2 mL per session.
Multiple complications such as rebleeding due to extrusion of the glue cast, systemic embolism,
gastric ulcer formation, major gastric variceal bleeding, and mesenteric hematoma associated with
hemoperitoneum and bacterial peritonitis, sepsis, stulas and pericarditis, chest pain and dysphagia
have been occasionally reported [7882].
Similar to what occurs with initial hemostasis, CA has been shown to be superior to both sclerotherapy and band ligation for secondary prophylaxis. On the contrary, comparison with non-selective
beta-blockers offers conicting results. In a small randomized study, 41 patients that bled from

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657

esophageal (n 31) or GV (GOV 1 and GOV 2)(n 10) treated initially with CA were randomized to
repeated CA injections (n 21) or propranolol (80160 mg) (n 20) [83]. No signicant differences
were observed between the 2 groups in the incidence of variceal rebleeding and death. The incidence
of complications was higher in the CA group (47% vs. 10%). A major limitation of the study was the small
number of patients with GV [83]. In a more recent RCT, 67 patients who bled from GV (54 GOV 2 and 10
IGV1) were allocated to receive either repeated CA (n33) or propranolol (n 34) for secondary
prophylaxis [84]. Rebleeding in the CA group was signicantly lower than in the beta-blocker group
(15% vs 55%, p 0.004) and after a 26 month follow up the mortality rate was lower as well (3% vs 25%,
p 0.026). The rate of complications in the CA group was 3%.
An alternative agent for endoscopic treatments is thrombin which converts brinogen to a brin
clot, thus forming a clot inside the GV and occluding blood ow [85]. The use of bovine thrombin was
banned due to the risk of potential prion transmission but now it is available human thrombin. Each
vial is reconstituted with 5 mL of distilled water for a concentration of 250 U/mL [86]. The average dose
of injected thrombin ranges between 1500 and 2000 U. Available data indicates that thrombin is safe
and effective in the treatment of acute GV bleeding with hemostasis rates of 70100%, however
rebleeding rates may range from 7 to 50% [85,8791]. No clear data have been published regarding
follow up and eradication rates. After initial hemostasis, repeated thrombin injections are performed
every 23 weeks until eradication. Given the paucity of data mostly coming from case series, the
routine use of thrombin cannot be routinely recommended.
TIPS
TIPS is a very effective treatment for GV bleeding with more than a 90% success rate for initial
hemostasis and a low rebleeding rate. Three studies compared the use of TIPS vs CA in GV bleeding [92
95]. These studies demonstrated no major differences in the rate of initial hemostasis between the two
therapies. Two of these studies [93,94] showed a higher rebleeding rate in the CA group (30 and 59%)
vs. the TIPS group (15 and 40%). Frequency of complications were similar in the two groups but TIPS
treated patients showed a higher incidence of hepatic encephalopathy [9395] and long-term
morbidity requiring hospitalization [94] than endoscopically treated patients. The studies found no
signicant differences in survival. In summary, TIPS is a very effective therapy to prevent GV rebleeding.
Nevertheless, more data is needed to clarify the role of TIPS in the secondary prophylaxis of GV
bleeding and determine if this therapy must be universally applied or reserved as a rescue therapy after
failure of more conservative approaches.
Surgery
Derivative surgery although effective is rarely used due to the wide availability of less invasive
techniques such as endoscopy and interventional radiology. In selected cases, patients with gastric
varices and segmental/left-sided portal hypertension due to isolated splenic vein thrombosis may be
candidates for splenectomy or splenic embolization as a means of denitive therapy, however data is
scarce.
Balloon-occluded retrograde transvenous obliteration
Since its introduction by Kanagawa et al [96], balloon-occluded retrograde transvenous obliteration
(BRTO) has become widely accepted in Japan and in some centers in USA as a minimally invasive and
highly effective treatment for GV. Ethanolamine oleate is the predominant and traditional sclerosant
agent used in the BRTO procedure, particularly in Asia. Detergent sclerosants in a foam or froth have
also been studied in both Japan (polidocanol) [97,98] and the United States (3% STS) [99]. Gastric varices
usually disappear after 23 months ([71]).
The most common complications of BRTO are epigastric and back pain (76%) [100], fever (26%)
[100,101], and transient hematuria (53%). Portal (4.3%) and renal vein thrombosis (5%) can be found in a
small number of patients and both are usually clinically silent [102] [103,104]. Pulmonary embolism
[104], pulmonary edema [97], coil migration [103] and anaphylaxis to ethanolamine oleate [103] have
also been reported.
Technical success, dened by complete obliteration of the GV with sclerosant, occurs in 77100% of
patients [105]. In some studies, repeat BRTO was necessary to achieve such high percentages. GV

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bleeding after a successful BRTO ranges from 0 to 15% or from 0 to 31.6% when factoring in an intent-totreat basis (including technical failures). Some authors suggest that BRTO might be better than TIPS
[106] or glue [107] in the prevention of GV bleeding. However, the fact that in most patients treatment
was administered as primary prophylaxis for high risk GV, the studies had a small sample size, and the
efcacy of the comparative groups (either TIPS or glue therapy) was poorer than expected, precludes
denitive conclusions. There is only a small study [108] that randomized 15 patients with acute GV
bleeding to receive TIPS (n 7) or BRTO (n 8) without observing signicant differences in the
rebleeding, hepatic encephalopathy or survival.
In contrast to TIPS, which is known to divert blood ow from hepatic parenchyma and may worsen
liver function in some patients, successful BRTO theoretically augments perfusion of the hepatic parenchyma and may improve indices of hepatic function. On the other hand, increasing portal pressure
can cause signicant aggravation of portal hypertensive complications such as ascites, hepatic hydrothorax and variceal bleeding. In some cases, these problems may require subsequent TIPS placement [71].
In conclusion, although BRTO seems to be a feasible technique able to successfully control and
prevent GV bleeding, there is a lack of good quality data to establish the actual place of BRTO on the
management of GV [71]. BRTO could be considered in patients with GV bleeding and large gastrorenal
shunts that have contraindications for the use of TIPS.
Portal hypertensive gastropathy and GAVE
Portal hypertensive gastropathy (PHG) and gastric antral vascular ectasia (GAVE) are two different
clinical conditions that [109] both can cause chronic gastrointestinal hemorrhage in patients with
cirrhosis, manifested by chronic anemia.
PHG
PHG is the most frequent of the two entities with a prevalence between 11 and 80%, it is more often
observed in patients with more severe liver disease [110,111] and in patients with cirrhosis who have
had previous endoscopic treatment with sclerotherapy or endoscopic variceal ligation [112114]. The
diagnosis of PHG is endoscopic and it is graded by macroscopic ndings as mild (mosaic-like pattern),
and severe (red-point lesions/cherry-red spots/black-brown spots) [10], and is more often observed in
the fundus and corpus of the stomach. The incidence of acute bleeding is low (less than 3% at 3 years)
with a mortality of 12.5%; for chronic bleeding the incidence is around 1015% at 3 years.
In acute bleeding, NSBB, somatostatin, octreotide, vassopressin, terlipressin, and estrogens have
been proposed based on their ability to decrease gastric perfusion in this context [109]. Up to date nonselective beta-blockers should be used in the chronic setting once the acute episode of bleeding is
controlled and the patient is stable [115].
In patients requiring frequent transfusions, TIPS has been successfully used [109].
Lately it has been evaluated the use of argon plasma coagulation (APC) in the treatment of PHG. In a
small cohort of patients with chronic PHG bleeding APC treatment resulted in absence of upper GI
bleeding or reduction of transfusion requirements in 81% of patients. Perhaps those patients who do
not respond to betablockers, have severe recurrent bleeding and are not candidates for TIPS could be
considered for APC [109].
GAVE
GAVE, also known as watermelon stomach, is endoscopically characterized by red patches and spots
in a diffuse or linear distribution in the gastric antrum. GAVE is detected less frequently compared to
PHG, having been reported in only 2% [116], of patients awaiting liver transplantation or 3% of patients
with HCV and advanced brosis [111]. Only 30% of GAVE cases occur in patients with portal hypertension meaning that GAVE should not be considered a portal hypertension-specic feature. In fact,
GAVE can be observed also in patients with other non-hepatic chronic diseases such as autoimmune
connective tissue disorders, bone marrow transplantation and chronic renal failure [109].

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659

GAVE should be distinguished from severe PHG [117] owing to their different response to the
treatment of portal hypertension. While NSBB and TIPS can be used in severe PHG causing signicant
blood losses, GAVE is unresponsive to these treatments [118].
Endoscopic treatment of GAVE lesions is the main treatment for symptomatic lesions while it is
reasonable to not treat lesions that are asymptomatic [109]. APC is the most common used technique
and it should be repeated until all lesions are fully treated. If endoscopic therapy is not effective or it is
not feasible, other options for which there is very limited experience can be considered. Few and not
very recent studies suggested that the use of estrogen-progesterone may be useful [119,120]. Some
success has been described in case reports with the use of octreotide, corticosteroids, tranexamic acid,
thalidomide and a serotonin antagonist [109].

Practice points
- Endoscopic screening for esophageal varices should be performed in every cirrhotic patient. It
should be performed every 23 years in patients without varices and every 12 years if small
varices are found and beta-blockers are not initiated. No follow-up endoscopy is needed once
beta-blockers are started.
- Non selective beta-blockers and EBL are both effective in the prevention of rst bleeding.
- General management of the bleeding episode includes careful blood volume replacement,
securing airway, antibiotic prophylaxis and early administration of vasoactive drugs. An
endoscopy should be performed within rst 12 h. EBL is better than sclerotherapy in the
initial control of bleeding.
- Early-TIPS using covered stents must be considered in patients at high risk of failure receiving
the above mentioned treatment (Child B with active bleeding and Child C up to 13).
- Prevention of re-bleeding is mandatory. Combination therapy (drugs EBL) is recommended. TIPS should be considered as a rescue therapy.
- Gastric varices (GV) represent 510% of all upper digestive bleeding episodes in cirrhosis.
- The most useful endoscopic treatment for acute GV bleeding is tissue adhesives injection.
Further tissue injections, NSBB or TIPS have been shown to be effective preventing
rebleeding.
- Balloon-occluded retrograde transvenous obliteration should be considered in treatment
failures and that are not candidates for TIPS.

Research agenda
- Large longitudinal survey studies conrming the role of Early-TIPS in acute variceal bleeding.
- Dening additional populations with acute variceal bleeding and a high-risk of treatment
failure that may benet from Early-TIPS.
- Dene the role of carvedilol in the prophylaxis of rst variceal bleeding or re-bleeding.
- Identifying patients at high-risk of failure applying NSBB EBL for the prevention of
rebleeding that may benet from other more invasive treatments.
- Comparing with adequately designed trials the use of self-expanding esophageal stents vs
balloon tamponade in acute variceal bleeding.
- Evaluation of NSBB in GV primary prophylaxis.
- Establish the best treatment for acute Gastric variceal bleeding and for the prevention of GV
rebleeding.

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F. Turon et al. / Best Practice & Research Clinical Gastroenterology 27 (2013) 649664

Conict of interest statement

JC Garcia-Pagan receives speakers fees from GORE. No other conicts of interest.

Acknowledgments
Supported by a grant from the Ministerio de Economia y Competitividad (SAF 2010/17043) Spain.
CIBERehd is funded by the Instituto de Salud Carlos III.

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