Portal Hypertension and Gastrointestinal Bleeding

Transcription

Portal Hypertension and Gastrointestinal
Bleeding
Jaime Bosch, M.D., Ph.D.,1,2 Juan G. Abraldes, M.D.,1,2
Annalisa Berzigotti, M.D.,3,4 and Juan Carlos Garcia-Pagan, M.D.1,2
ABSTRACT
Variceal bleeding is one of the most serious complications of portal hypertension.
The driving force for the development of varices is an increase in portal pressure. As portal
hypertension progresses, varices dilate until they finally rupture and bleed. This sequence of
events might be prevented by achieving a sufficient decrease in portal pressure or by acting
locally at the varices with endoscopic treatments. This article reviews the rationale for the
management of portal hypertension and the current recommendations for the prevention
and treatment of variceal bleeding.
KEYWORDS: Cirrhosis, varices, endoscopic band ligation, TIPS, b-adrenergic blockers,
hepatic venous pressure gradient
P
ortal hypertension is a common clinical syndrome defined by a pathologic increase of portal venous
pressure. As a consequence, the gradient between portal
pressure (PP) and inferior vena cava pressure (IVC)
(portal pressure gradient, PPG) is increased above the
upper normal value of 5 mm Hg. Portal hypertension can
be due to many different causes, at prehepatic, intrahepatic, and posthepatic sites (Table 1). Cirrhosis of the
liver accounts for 90% of cases of portal hypertension
in Western countries.
The importance of portal hypertensive syndrome
is defined by the frequency and severity of its complications, including upper gastrointestinal bleeding from
ruptured gastroesophageal varices, ascites, and hepatorenal syndrome, which represent the leading causes
of death and of liver transplantation in patients with
cirrhosis. This article focuses on esophageal varices and
gastrointestinal bleeding in cirrhosis.
Portal hypertension is considered to be clinically
significant (CSPH) when PPG, or its clinical equivalent
hepatic venous pressure gradient (HVPG), exceeds 10 to
12 mm Hg, since this is the threshold for the clinical
manifestations of portal hypertensive syndrome to appear. The vast majority of patients with cirrhosis develop
CSPH along the course of the disease, and data from a
recent multicentric study indicate that CSPH is already
present at diagnosis in 60% of histologically proven,
well-compensated cirrhosis cases.1
1
Bosch, M.D., Ph.D., Hepatic Hemodynamic Laboratory, Liver Unit,
Hospital Clıńic, Villarroel 170, 08036 Barcelona, Spain (e-mail:
[email protected]).
Complications of Cirrhosis; Guest Editor, Pere Gine`s, M.D.
Semin Liver Dis 2008;28:3–25. Copyright # 2008 by Thieme
Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001,
USA. Tel: +1(212) 584-4662.
DOI 10.1055/s-2008-1040318. ISSN 0272-8087.
Hepatic Hemodynamic Laboratory, Liver Unit, Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS), University of
Barcelona, Spain; 2Centro de Investigacioń Biome´dica en Red de
Enfermedades Hepa´ticas y Digestivas (CIBEREHD), University of
Barcelona, Spain; 3Centre Diagnostic per la Imatge, Hospital Clinic,
Barcelona, Spain; 4Department of Internal Medicine, Cardioangiology, Hepatology, Policlinico S. Orsola, University of Bologna, Italy.
Address for correspondence and reprint requests: Professor Jaime
NATURAL HISTORY AND PROGNOSIS
Variceal bleeding is the last step of a chain of events
initiated by an increase in PP, followed by the development and progressive dilation of varices until these
finally rupture and bleed. According to recent data,2
the appearance of varices in compensated patients indicates a change from a clinical stage with a very low risk
of death at 1 year (stage 1; 1% risk) to an intermediaterisk stage (stage 2; 3.4% risk). The occurrence of variceal
bleeding is a dreadful event, marking the progression to
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SEMINARS IN LIVER DISEASE/VOLUME 28, NUMBER 1
2008
Table 1 Etiology of Portal Hypertension According to
the Site of Increased Resistance to Portal Blood Flow
Prehepatic
development of varices,1 confirming that PP plays a
pivotal role as the driving force for the development of
collaterals.
Splenic vein thrombosis
Portal vein thrombosis
Congenital stenosis of the portal vein
Extrinsic compression of the portal vein
Arteriovenous fistulae
Intrahepatic
Cirrhosis (viral, alcoholic, biliary, metabolic)
Partial nodular transformation
Nodular regenerative hyperplasia
Congenital hepatic fibrosis
Peliosis hepatic
Polycystic disease
Idiopathic portal hypertension
Hypervitaminosis A
Arsenic, copper sulfate, vinyl chloride monomer poisoning
Granulomatous diseases (sarcoidosis, tuberculosis, primary
biliary cirrhosis, schistosomiasis)
Amyloidosis
Mastocytosis
Rendu-Osler-Weber syndrome
Liver infiltration in hematologic diseases
Acute fatty liver of pregnancy
Progression of Esophageal Varices from Small
to Large
Once developed, varices increase in size from small to
large before they eventually rupture and bleed. Studies
assessing the progression from small to large varices are
controversial, showing rates of progression of varices
ranging from 5 to 30% per year.7–10 The most likely
reasons for such variability are differences in patient
selection and follow-up endoscopy schedule.10 The factor that has been most consistently associated with
variceal progression is Child-Pugh class.7–9,11 Other
factors include alcoholic etiology of cirrhosis and presence of red wale markings in the esophageal varices.8,10
Changes in HVPG (either ‘‘spontaneous’’ or caused by
drug therapy or transjugular intrahepatic portal-systemic
shunts [TIPS]) are usually accompanied by parallel
variations in the size of the esophageal varices, which
are significantly reduced when HVPG decreases below
12 mm Hg.12,13 Thus, an increased HVPG plays a key
role both in development and progression of the varices.
Severe acute viral and alcoholic hepatitis
Chronic active hepatitis
Hepatocellular carcinoma
Cyanamide toxicity
Veno-occlusive disease
Posthepatic
Hepatic veins thrombosis (Budd-Chiari syndrome)
Congenital malformation and thrombosis of the inferior
vena cava
Constrictive pericarditis
Tricuspid valve diseases
decompensation of the liver disease and to a very high
risk of death stage (stage 4; 57% risk) (Fig. 1).
Prevalence and Formation of Esophageal
Varices
When cirrhosis is first diagnosed, varices are present in
30 to 40% of compensated patients and in 60% of
decompensated.1,3,4 Clinical-hemodynamic correlations
have shown that varices may appear when HVPG
increases to over 10 mm Hg.1,5 Since portal hypertension
eventually develops in almost every patient with cirrhosis
it is thought that, if cirrhotic patients are followed long
enough, virtually all of them will develop varices.6
In those cirrhotic patients without varices at first
endoscopy, the annual incidence of new varices is a mean
of 7%, ranging from 5 to 10% in published series.6–8 An
HVPG over 10 mm Hg is a strong predictor for the
Incidence and Risk Indicators of First Bleeding
from Esophageal Varices
First variceal bleeding has an incidence of 4% per year;
this risk increases to 15% per year in patients with
medium-large varices.4
The most important predictive factors related to
the risk of bleeding are variceal size, severity of liver
dysfunction as assessed by the Child-Pugh classification,
and presence of red signs.14 Variceal size and red color
signs are associated with increased bleeding risk probably
because they reflect direct parameters determining variceal wall tension (radius, wall thickness), which is the
decisive factor determining variceal rupture. In addition,
many studies have shown that variceal bleeding only
occurs if the HVPG reaches a threshold value of 12 mm
Hg.5,12,15 Conversely, if the HVPG is substantially
reduced (below 12 mm Hg or by more than 20% of
baseline levels), there is a marked reduction in the risk of
bleeding.12,16 This is of outstanding importance, since
it demonstrates that the portal hypertension syndrome
is reversible by pharmacological treatment effectively
decreasing PP (Fig. 2).
DIAGNOSIS
HVPG Measurement
Measurement of HVPG by hepatic vein catheterization
is an objective and quantitative equivalent of PP in
PORTAL HYPERTENSION AND GI BLEEDING/BOSCH ET AL
Figure 1 Clinical stages of cirrhosis according to clinical features Four clinical stages can be identified, each with distinct
clinical characteristics and a markedly different prognosis. Each stage is defined by the presence or absence of complications of
cirrhosis. As shown, the onset of esophageal varices in compensated patients indicates a change from a clinical stage with a
very low risk of death at 1 year to an intermediate risk stage, while the occurrence of variceal bleeding situates the patient in the
highest risk stage. (Modified from D’Amico G, Garcia-Tsao G, Pagliaro L. Natural history and prognostic indicators of survival in
cirrhosis: a systematic review of 118 studies. J Hepatol 2006;44:217–231).174
cirrhosis.17 HVPG has proved to add prognostic information in many settings, including compensated cirrhosis,18 acute variceal bleeding,19 and patients awaiting
liver transplantation.20
However, as previously mentioned, not all patients with increased HVPG have varices. Patients with
CSPH are at high risk of varices and should undergo
endoscopic screening.
Endoscopy
The current consensus is that every cirrhotic patient
should be endoscopically screened for varices at the
time of diagnosis.21 The aim of the screening for
esophageal varices is to detect patients requiring prophylactic treatment.
In patients without varices on initial endoscopy,
further evaluations should be performed to detect the
Figure 2 Natural history of esophageal varices as a function of variceal wall tension. The solid line shows the evolution of
untreated patients: variceal wall tension increases markedly as a result of an increase of hepatic venous pressure gradient (HVPG)
above 10 mm Hg, enlargement of the varix, and decrease of wall thickness. Once wall tension increases to values exceeding the
elastic limit of the vessel, the patient may experience his or her first bleeding episode. Afterward, the patient remains at risk
unless wall tension is decreased by means of medical therapy (decrease of HVPG to < 12 mm Hg or by > 20% versus baseline
value) (discontinuous line). Primary prophylaxis (dotted line) prevents or delays wall tension from reaching the rupture point, so
reducing the bleeding risk. (Modified from Escorsell A, Bosch J. Pathophysiology of variceal bleeding. In: Groszmann RJ, Bosch J,
eds. Portal Hypertension in the 21st Century. Dordrecht/Boston/London: Kluwer Academic Publishers; 2004:155–166.)
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development of varices. The current consensus is that
endoscopy should be repeated after 2 to 3 years in
patients without varices at the first endoscopy. The
expected incidence of moderate/large varices and/or
variceal bleeding in these patients (and, thus, the risk
of leaving patients without prophylaxis) is less than 10%
at 3 years.8,10 In those centers in which hepatic hemodynamic studies are available it is advisable to measure
HVPG. An HVPG over 10 mm Hg indicates a more
rapid progression to complications of cirrhosis, and calls
for shorter surveillance intervals.22
In patients with small varices on initial endoscopy, the aim of subsequent evaluations is to detect the
progression of small to moderate/large varices because of
its important prognostic and therapeutic implications.
Based on an expected 10 to 15% per year rate
of progression of variceal size, endoscopy should be
repeated every 2 years in patients with small varices.
In patients with advanced cirrhosis or red wale marks, a
1-year interval might be recommended.8,10
Endoscopic Videocapsule
Patients are frequently intolerant to repeated conventional
endoscopies, and often require sedation. Recently, endoscopic videocapsule has been suggested, as this may
improve patients’ tolerance. Once swallowed, the videocapsule records images at predetermined intervals. In the
two published studies, capsule endoscopy allowed a correct
identification of varices in 80% of cases23,24; in one of
these studies, capsule endoscopy proved a correct identification of red wale marks.23 However, it may not be as
good in assessing variceal size and it may have poor
accuracy in identifying the presence of hypertensive gastropathy and gastric varices.25 Therefore, endoscopic videocapsule cannot be currently recommended as the routine
screening method for the evaluation of gastroesophageal
varices or portal hypertensive gastropathy in cirrhosis.
Noninvasive Tests
The ideal method to diagnose and follow up portal
hypertension should be reproducible, inexpensive, and
noninvasive (Fig. 3). No noninvasive procedure has
proved, so far, to be accurate enough to avoid endoscopy
in patients with negative indicators.26,27 However, some
clinical, laboratory, and imaging variables may help to
select patients with high risk for varices.28,29
CLINICAL SIGNS AND LABORATORY FINDINGS
The presence of splenomegaly, or enlarged spleen size,
is the clinical sign most often reported in studies on
Figure 3 Existing diagnostic tools in the clinical assessment of portal hypertension. The ideal method to diagnose portal
hypertension should be noninvasive, accurate, objective, and reproducible. HVPG, hepatic venous pressure gradient; CT,
computed tomography; MRI, magnetic resonance imaging; CDUS, color-Doppler ultrasonography.
noninvasive prediction of portal hypertension and
esophageal varices. Platelet count, and platelet to spleen
ratio,29 have been suggested as useful to select patients
with high probability of having large esophageal varices.
However, the cut-offs vary a lot across studies (platelet
count from 68,000 to 160,000/mm3), indicating low
specificity. In addition, in viral cirrhosis, platelet count
can decrease independently from the development of
portal hypertension. Other laboratory data independently correlated with the presence of varices or large
varices are indicators of liver failure, such as hypoalbuminemia, low prothrombin time, and hyperbilirubinemia,30 or their combination in the Child-Pugh score.31
Some indicators of liver fibrosis, such as hyaluronic
acid level32 or the Fibrotest, have also been suggested
to correlate with the presence of esophageal varices.
IMAGING TECHNIQUES
Ultrasonography (US)/color Doppler-US (CDUS) is
the preferred initial examination in patients with suspected portal hypertension. US can detect signs of portal
hypertension such as splenomegaly, presence of portocollateral vessels, and ascites, and complement this information with data on liver size, echotexture, and
margins, which can suggest underlying cirrhosis. Among
the US parameters, spleen length is the strongest independent predictive marker of esophageal varices. Portal vein diameter (above 13 mm), portal blood flow
velocity (mean velocity below 12 cm/s),33 lack or reduced
respiratory variations of splenic and superior mesenteric
vein diameter,34 congestion index of portal vein, altered
hepatic venous Doppler pattern, increased intraparenchymal hepatic and splenic artery impedance,35 increased
intraparenchymal renal artery impedance,36 and reduced
mesenteric artery impedance37 have all been found to
correlate with the presence of CSPH and esophageal
varices. However, these variables do not show a satisfactory predictive accuracy in independent sets of
patients, probably due to the high interobserver and
intraobserver variability.
Computed tomography (CT) scan and MRI
(magnetic resonance imaging) allow a good visualization
of the portal venous system, and both techniques permit
the diagnosis of esophageal varices.38,39 The measurement of azygos blood flow by angio-MR has shown a
correlation with the presence of esophageal varices and
the risk of variceal bleeding. However, the technical
complexity and cost of these techniques makes their
use unlikely for the screening of gastroesophageal varices
in cirrhosis.
LIVER STIFFNESS (FibroScan)
Transient elastography (FibroScan1) is a noninvasive
method recently developed for assessing liver fibrosis.40
Because fibrosis and scarring of the liver tissue are major
factors contributing to the development of portal hyper-
tension, liver stiffness measurement has theoretical potential for the evaluation of portal hypertension. Recent
studies demonstrate that liver stiffness shows a good
correlation with HVPG: in a study in liver transplant
recipients with hepatitis C virus recurrence, a liver stiffness value 8.74 kPa had a sensitivity and specificity of
90% and 81% for the diagnosis of increased PP (HVPG
6 mm Hg).41 In three different studies, two published
as abstracts42,43 and one as a full paper,44 the authors
found that liver stiffness can detect accurately an HVPG
over 12 mm Hg in patients with cirrhosis or long-lasting
chronic liver disease. However, different cut-off values
were found, namely 17 kPa, 23 kPa, and 13.6 kPa.
Interestingly, in the study by Vizzutti and colleagues,44
it was shown that above the threshold value of 13.6 kPa
there was not a good correlation between liver stiffness
and HVPG, probably since structural abnormalities
within the liver (e.g., fibrosis) are not the only mechanisms promoting portal hypertension, which is also
determined by the magnitude of portocollateral blood
flow and changes in hepatic vascular tone (which are
not reflected by the Fibroscan).
As for the prediction of esophageal varices, the
study by Kazemi and associates suggested that liver
stiffness might be used to select those patients likely to
have large varices and requiring screening endoscopy.45
In this study, however, endoscopic assessment was retrospective, and transient elastography performed no better
than other simple noninvasive variables that are routinely
obtained in these patients, such as blood test and ultrasonography. Additionally, transient elastography was
not discriminative to detect small varices, since the best
cut-off for detecting all types of varices overlapped with
that for detecting cirrhosis.46
Further studies are therefore needed before
recommendation can be given on the routine use of
Fibroscan for the detection of CSPH and varices.
RATIONAL BASIS OF THERAPY
In cirrhosis, portal hypertension is due to increased
resistance to portal blood flow through the cirrhotic
liver, and increased blood flow in the portal and collateral
circulation. Portal hypertension can therefore be attenuated by decreasing intrahepatic resistance, reducing portocollateral blood flow, or both47 (Fig. 4). These targets
can be addressed by means of medical treatment, local
treatments, or derivative procedures.
The initial factor in the pathophysiology of portal
hypertension is the increase in vascular resistance to
portal blood flow. In cirrhosis this increase in resistance
occurs at the hepatic microcirculation (sinusoidal portal
hypertension). Increased hepatic vascular resistance in
cirrhosis is not only a mechanical consequence of the
hepatic architectural disorder caused by the liver disease,
as there is also a dynamic component due to the active
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Figure 4 Rational basis of therapy. A mechanical increase in hepatic resistance due to structural alterations of liver
parenchyma is the initial factor that leads to portal hypertension. This might be overcome by TIPS placement. The recognition
of a functional and, thus, reversible component in the increased hepatic resistance sets the rationale for the use of vasodilators
in portal hypertension. Furthermore, portal hypertension leads to a cascade of disturbances in the splanchnic and systemic
circulation characterized by vasodilation, sodium and water retention, and plasma volume expansion that lead to an increase in
portal blood inflow that contributes to maintain and worsen portal hypertension. This sets the rationale for the use of
vasoconstrictors and diuretics in the treatment of portal hypertension. Varices are the result of the development of
portosystemic collaterals. Endoscopic treatments are directed at locally ‘‘eradicating’’ the varices, but do not decrease portal
pressure. TIPS, transjugular intrahepatic portal-systemic shunts; PSS, portal-systemic shunt; CO, carbon monoxide; NE,
norepinephrine; VP, vasopressin; A-II, angiotensin-II; Na, sodium.
contraction of portal/septal myofibroblasts, activated
hepatic stellate cells, and vascular smooth muscle cells
in portal venules.48 This increased hepatic vascular tone
is due to an imbalance between endogenous vasodilatory
and vasoconstrictor stimuli, the former being insufficient
to counteract the influence of the latter.49 Indeed, while
vasoconstrictors are increased, intrahepatic nitric oxide
(NO) production is clearly decreased.49,50 This deficient
intrahepatic NO production is due to endothelial dysfunction in the liver microvascultature50,51 and may also
favor local thrombosis and fibrogenesis.49 This finding
provides a rational basis for drug therapies aimed at
increasing NO within the liver either by the use of NO
donors or by enhancing e-NOS activity with statins.
Oxidative stress is in part responsible for reduced intrahepatic NO bioavailability, which provides a rational
basis for testing antioxidants, such as ascorbic acid.52
The increased resistance through the cirrhotic
liver can also be targeted by ‘‘mechanical’’ means, bypassing the liver. This can be achieved by portal-systemic
shunt surgery and by TIPS. These procedures are highly
effective in decreasing PP, but have the detrimental
effect that, by further decreasing portal blood flow
through the liver and by increasing portal-systemic
shunting, they may enhance liver failure and facilitate
hepatic encephalopathy.
The second factor contributing to portal hypertension is an increased blood flow through the portal
venous system. This is due to splanchnic arteriolar
vasodilation, probably due to excessive release of endogenous vasodilators (endothelial and neurohumoral).53–55
Splanchnic hyperemia contributes to the increase in PP
and explains why portal hypertension persists, despite
the establishment of an extensive network of portosystemic collaterals that may divert over 80% of the portal
blood flow. The increased portal venous inflow can be
corrected pharmacologically by means of splanchnic
vasoconstrictors, such as vasopressin and its derivatives,
somatostatin and its analogues, and nonselective badrenergic blockers. These are the drugs that have
more widely been used in the treatment of portal hypertension. Splanchnic vasodilation is in part due to an
increased release of NO in splanchnic arteries, which
is amenable to pharmacological manipulation. However,
this presents the difficulty of inhibiting NO synthesis
selectively in the splanchnic arterial bed, which is
not feasible at present. Splanchnic vasodilation is accompanied by increased cardiac index and hypervolemia,
representing the hyperkinetic circulatory syndrome associated with portal hypertension. An expanded
blood volume is necessary to maintain the hyperdynamic
circulation, which provides a rationale for the use of
low-sodium diet and spironolactone to attenuate the
hyperkinetic syndrome and the PP elevation in patients
with cirrhosis.56
Combined pharmacological therapy consists in
associating vasoconstrictive drugs, which will decrease
portal blood inflow, and vasodilators, which may reduce
the intrahepatic vascular resistance. The best-known
example is the association of propranolol or nadolol
and isosorbide-5-mononitrate (ISMN).
Therapeutic strategies aimed at decreasing PP
have the advantage of potentially preventing other portal
hypertension-related complications, such as portal hypertensive gastropathy, ascites, spontaneous bacterial
peritonitis, and hepatorenal syndrome.
Local treatments at the varices complete the
spectrum of treatments for complications of portal hypertension. These treatments do not decrease PP and
therefore have no potential for preventing other complications of portal hypertension. Endoscopic therapy is
directed at eradicating the varices either by injecting a
variety of irritating substances into or around the varices
to promote thrombosis and fibrosis, or by ligating the
varices using elastic bands. It is possible that the efficacy
of endoscopic therapy can be enhanced if combined with
an agent that effectively lowers PP.
Finally, hemostatic agents, such as recombinant
activated factor VII, are being explored as adjuvants
to conventional therapy to arrest variceal bleeding in
patients with poor liver function.57,58
Clinical Scenarios
The treatment of portal hypertension includes the prevention of variceal hemorrhage in patients who have
never bled, the treatment of the acute bleeding episode,
and the prevention of rebleeding in patients who have
survived a bleeding episode from esophageal or gastric
varices. The main difference among these scenarios is
that natural history and prognosis are quite different
from one to another.
THE ACUTE BLEEDING EPISODE
Natural History and Prognosis
Ruptured esophageal varices cause 70% of all upper
gastrointestinal bleeding episodes in patients with portal
hypertension.59 Thus, in any cirrhotic patient with acute
upper gastrointestinal bleeding, a variceal origin should
be suspected. Diagnosis is established at emergency
endoscopy based on observing one of the following: (1)
active bleeding from a varix (observation of blood spurt-
ing or oozing from the varix) (nearly 20% of patients);
(2) white nipple or clot adherent to a varix; (3) presence
of varices without other potential sources of bleeding.
INITIAL CONTROL OF BLEEDING
Because variceal bleeding is frequently intermittent, it is
difficult to assess when the bleeding stops and when a
new hematemesis or melena should be considered an
episode of rebleeding. Several consensus conferences
have addressed this issue and set definitions for events
and timing of events related to episodes of variceal
bleeding.21 Using these definitions, data from placebo
controlled clinical trials show that variceal bleeding is
spontaneously controlled in 40 to 50% of patients.60
Currently available treatments increase control of bleeding to 80% of the patients.59
EARLY REBLEEDING
The incidence of early rebleeding ranges between 30%
and 40% in the first 6 weeks. The risk peaks in the first
5 days, with 40% of all rebleeding episodes occurring in
this very early period, remains high during the first 2
weeks, and then declines slowly in the next 4 weeks.
After 6 weeks the risk of further bleeding becomes
virtually equal to that before bleeding.61 Currently
available treatments have reduced the 6-week rebleeding
rate to 20%.59 Early rebleeding is a strong predictor of
death from variceal bleeding. Prognostic indicators for
early rebleeding were assessed in most studies together
with initial failure to control bleeding and 5-day risk
for death, forming a composite end point referred
to as ‘‘5-day failure.’’ Bacterial infection,62,63 active
bleeding at emergency endoscopy,59,63 Child-Pugh class
or score,59,63,64 AST levels,59 presence of portal vein
thrombosis59 and an HVPG > 20 mm Hg measured
shortly after admission19,64,65 have been reported as
significant predictors of risk for 5-day failure.
MORTALITY
Mortality from variceal bleeding has greatly decreased in
the last two decades, from 42% mortality in the Graham
and Smith study in 198161 to the current 15 to 20%.59,66–
68
This is probably due to implementation of effective
treatments (endoscopic and pharmacological therapies
and TIPS), as well as improved general medical care (i.e.,
antibiotic prophylaxis). Since it may be difficult to assess
the true cause of death (i.e., bleeding versus liver failure
or other adverse events), the general consensus is that
any death occurring within 6 weeks from hospital
admission for variceal bleeding should be considered as
a bleeding-related death.21 Immediate mortality from
uncontrolled bleeding is in the range of 4 to 8%.4,59
Prehospital mortality from variceal bleeding might be
around 3%.69 Like the risk for rebleeding, the risk for
mortality peaks the first days after bleeding, slowly
declines thereafter, and after 6 weeks becomes constant
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and virtually equal to that before bleeding.60,61 At
present, only 40% of the deaths are directly related to
bleeding, while most are caused by liver failure, infections, and hepatorenal syndrome.59 Thus, although there
is still room for improving hemostatic treatments, to
substantially decrease mortality from variceal bleeding,
therapies should be able to prevent deterioration of liver
and renal function.
The most consistently reported death risk indicators are Child-Pugh classification or its components,
blood urea nitrogen or serum creatinine, active bleeding
on endoscopy, hypovolemic shock, and hepatocellular
carcinoma.59,61,62,70 Prognostic indicators gathered in
the early follow-up include early rebleeding, bacterial
infection, and renal failure.70 From these data it is clear
that management of bleeding cirrhotic patients should
be aimed not only at controlling the bleeding, but also
at preventing early rebleeding, infection, and renal
failure.
Treatment of Acute Variceal Bleeding
Acute variceal bleeding should be managed in an intensive care setting by a team of experienced medical
staff, including well-trained nurses, clinical hepatologists, endoscopists, interventional radiologists, and surgeons. Lack of an appropriate facility or staff demands
immediate referral. Decision-making shall follow the
guidelines set up in a written protocol developed to
optimize the resources of each center.
GENERAL MANAGEMENT
The general management of the bleeding patient is
aimed at correcting hypovolemic shock (with judicious
volume replacement and transfusion) and at preventing
complications associated with gastrointestinal bleeding
(bacterial infections, hepatic decompensation, renal
failure), which are independent of the cause of the
hemorrhage and demand immediate management.
Initial resuscitation should follow the classic
Airway, Breathing, Circulation scheme, and is aimed at
restoring an appropriate delivery of oxygen to the tissues
(which depends on SaO2, cardiac output, and hemoglobin concentration).
Airway should be immediately secured, especially
in encephalopathic patients, since the patient is at risk of
bronchial aspiration of gastric content and blood. This
risk is further exacerbated by endoscopic procedures.
Endotracheal 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 mm Hg. Avoiding prolonged hypotension is particularly important to prevent infection
and renal failure, which are associated with increased risk
of rebleeding and death.70 Transfusion policy should be
conservative, since it may induce rebound increases in PP
and rebleeding.71,72 The use of vasopressin analogues or
somatostatin blunt the increase in PP induced by volume
expansion.73,74 Blood transfusion should aim at maintaining the hematocrit at 0.21 to 0.24 (Hb 7 to 8 g/L),21
except in patients with rapid ongoing bleeding or with
ischemic heart disease. The role of platelet transfusion or
fresh frozen plasma administration has not been assessed
appropriately. The use of recombinant activated factor
VII (rVIIa, Novoseven1), which corrects prothrombin
time in cirrhotics,75 has been assessed in two randomized
controlled trials. The first trial showed, in a post hoc
analysis, that rFVIIa administration may significantly
improve the results of conventional therapy in patients
with moderate and advanced liver failure (stages B and C
of the Child-Pugh classification) without increasing the
incidence of adverse events.57 A more recent trial tested
rVIIa in patients with active bleeding at endoscopy and
with a Child-Pugh score 8 points. This trial failed to
show a benefit of rVIIa in terms of decreasing the risk of
5-day failure but improved 6-week mortality.58
Infection is a strong prognostic indicator in acute
variceal bleeding.63 The most frequent infections are
spontaneous bacterial peritonitis (50%), urinary tract
infections (25%), and pneumonia (25%). The use of
prophylactic antibiotics in patients with acute variceal
bleeding has been shown to reduce both the risk of
rebleeding76 and mortality.77 Therefore, antibiotics
should be given to all patients from admission. Quinolones are frequently used due to their easy administration
and low cost.78 In high-risk patients (hypovolemic
shock, ascites, jaundice, or malnutrition) intravenous
ceftriaxone has recently been shown to be superior to
oral norfloxacin.79
Variceal bleeding can trigger hepatic encephalopathy. However, there are no data to support the prophylactic use of lactulose or lactitol.21
SPECIFIC THERAPY FOR CONTROL OF BLEEDING
Initial therapy for acute variceal bleeding is based on
the combination of vasoactive drugs with endoscopic
therapy. Rescue therapies for failures include balloon
tamponade and portal-systemic shunts, either surgical or
TIPS.
Pharmacological Therapy Vasoactive drugs act to
reduce variceal pressure by decreasing variceal blood
flow. The selection of the drug depends on the local
resources. Terlipressin should be the first choice if
available, since it is the only drug that has been shown
to improve survival.60,80 Somatostatin, octreotide, or
vapreotide are the second choice.60,81 If these drugs are
not available, vasopressin plus transdermal nitroglycerin
is an acceptable option.60
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 when vasopressin is
associated with nitroglycerin. 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.82 Terlipressin may be initiated
as early as variceal bleeding is suspected at a dose of
2 mg/4 hours for the first 48 hours, and it may be
maintained for up to 5 days at a dose of 1 mg/4 hours to
prevent rebleeding.82 Compared with placebo or nonactive treatment, terlipressin significantly improves the
rate of control of bleeding and survival.83 This is the only
treatment that has been shown to improve prognosis of
variceal bleeding in placebo-controlled randomized clinical trials (RCTs) and meta-analysis.60,83 Terlipressin is
as effective as any other effective therapy, including
endoscopic injection sclerotherapy (EIS), and is safer
than vasopressin þ nitroglycerin and EIS.60,82,83 The
overall efficacy of terlipressin in controlling acute variceal
bleeding at 48 hours is 75 to 80% across trials,83 and 67%
at 5 days.82 Terlipressin is also useful in hepatorenal
syndrome.84 Thus the use of terlipressin for variceal
bleeding may prevent renal failure, which is frequently
precipitated by variceal bleeding.70
Somatostatin is commonly used as an initial bolus
of 250 mg followed by a 250-mg/h infusion that is
maintained until the achievement of a 24-hour bleedfree period. The bolus injection can be repeated up to
three times in the first hour if bleeding is uncontrolled.
Therapy may be further maintained for up to 5 days
to prevent early rebleeding.85 The use of higher
doses (500 mg/h) causes a greater fall in HVPG and
translates into increased clinical efficacy in the subset of
patients with more difficult bleedings (those with active
bleeding at emergency endoscopy).86 Major side effects
with somatostatin are rare. Minor side effects, such as
nausea, vomiting, and hyperglycemia occur in up 30% of
patients.85–87 Several randomized controlled trials
showed that somatostatin significantly improves the
rate of control of bleeding compared with placebo or
nonactive treatment.60,81 However, despite the beneficial
effect on control of bleeding, somatostatin did not
reduce mortality.60 Somatostatin has been compared
with terlipressin and no differences were found for failure to control bleeding, rebleeding, mortality, or in the
incidence of adverse events in both treatment groups.60
Octreotide is a somatostatin analogue with longer
half-life. This, however, is not associated with longer
hemodynamic effects than somatostatin.88 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.81 As with somatostatin, therapy can be maintained
for 5 days to prevent early rebleeding. The safety profile of
octreotide is close to that of somatostatin. The efficacy of
octreotide as a single therapy for variceal bleeding is
controversial. No benefit from octreotide was found in
the only trial using octreotide or placebo as initial treatment,89 which may be due to rapid development of
tachyphylaxis.88 However, RCTs using octreotide on
top of sclerotherapy have shown a significant benefit in
terms of reducing early rebleeding.90 It has been speculated that this may be related to its sustained ability to
prevent postprandial increase in PP.81 Mortality, however, was not affected.60,90 These results suggest that
octreotide may improve the results of endoscopic therapy
but has uncertain effects if used alone. When compared
with other vasoactive drugs, octreotide was better than
vasopressin and equivalent to terlipressin, again suggesting a clinical value from the use of octreotide, although all
these studies were underpowered and none was double
blind.60
Endoscopic Therapy Both sclerotherapy and endoscopic band ligation (EBL) have been shown to be
effective in the control of acute variceal bleeding. Two
randomized trials specifically compared band ligation
and sclerotherapy in acute variceal bleeding.91,92 In one
of them all patients also received pharmacological therapy (somatostatin).92 In eight additional trials these two
modalities were compared both in acute bleeding and in
the prevention of rebleeding. Meta-analysis shows that
EBL is better than sclerotherapy in the initial control of
bleeding, and is associated with fewer adverse events and
improved mortality. Additionally, sclerotherapy, but not
EBL, may induce a sustained increase in PP.93 Therefore
EBL should be the endoscopic therapy of choice in acute
variceal bleeding, though injection sclerotherapy is acceptable if band ligation is not available or is technically
difficult. Endoscopic therapy can be performed at the
time of diagnostic endoscopy, early after admission,
provided that a skilled endoscopist is available. This is
important since there has been an increased frequency
of aspiration pneumonia since emergency endoscopic
therapy has become a universal practice.
Current Recommendation for Initial Treatment The current recommendation is to combine
these two approaches, starting vasoactive drug therapy
early (ideally during the transfer to the hospital, even if
active bleeding is only suspected) and performing EBL
(or injection sclerotherapy if band ligation is technically
difficult) after initial resuscitation when the patient is
stable and bleeding has ceased or slowed (Table 2). The
rationale for that comes from several RCTs demonstrating that early administration of a vasoactive drug facilitates endoscopy and improves control of bleeding and
5-day rebleeding.80,87,94,95 Drug therapy also improves
the results of endoscopic treatment if started just after
sclerotherapy or band ligation.60,90 Conversely, the association of endoscopic therapy also improves the efficacy of
vasoactive treatment.87 However, this combined approach failed to significantly improve 6-week mortality with
11
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Table 2 Treatment of Acute Variceal Bleeding:
Recommendations
The best approach is the combined use of a pharmacological
agent, started from admission (or even during transfer
difficult to make a clinicallybased decision. Prognostic
scores99 may provide objective parameters to ease the
decision of not offering invasive treatments in difficult
cases.
to hospital), and an endoscopic procedure.
Terlipressin, somatostatin, octreotide, and
SPECIAL PROBLEMS IN MANAGEMENT
vasopressin þ nitroglycerin (in this order of preference) may be
used; drug therapy should be maintained for at least 2 to
5 days.
Endoscopic band ligation or injection sclerotherapy (in this
order of preference) are the endoscopic treatments of choice
in bleeding esophageal varices; in bleeding gastric varices
the best endoscopic choice is obturation with cyanoacrylate.
Prophylaxis of infection with broad spectrum antibiotics
should be given to all patients.
TIPS should be used as a rescue procedure when medical
and endoscopic therapies fail; patients bleeding from gastric
varices may require an earlier decision for TIPS.
TIPS, transjugular intrahepatic portal-systemic shunts.
respect to endoscopic therapy96 or a vasoactive drug87
alone. The optimal duration of drug therapy is not well
established and requires evaluation. Current recommendation is to maintain the drug for 2 to 5 days, to cover
the period of maximum risk of rebleeding.21
RESCUE THERAPIES: TAMPONADE, SURGERY, AND TIPS
In 10 to 20% 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 (if technically possible) might
be attempted. If this fails, or bleeding is severe, the
patient should be offered a derivative treatment, before
the clinical status of the patient further deteriorates.
Balloon tamponade achieves hemostasis in 60 to 90%
of variceal bleedings3 but should only be used in the case
of a massive bleeding, for a short period of time (less
than 24 hours) as a temporal ‘‘bridge’’ until definite
treatment is instituted. Bleeding recurs after deflation
in over half of the cases and severe complications are
common. A recent report suggests that the use of
esophageal covered stents might achieve hemostasis in
most patients with refractory bleeding,97 with the advantage over tamponade of less severe complications
despite much longer periods of treatment. Adequately
designed trials should confirm these findings.
Both TIPS and surgical shunts are extremely
effective for controlling variceal bleeding (control rate
approaches 95%), but due to worsening of liver function
and encephalopathy mortality remains high.3,98 TIPS is
the first choice, since most patients requiring rescue
treatment have advanced liver disease. However, rarely,
if ever, will a patient with a Child-Pugh score over 13
survive TIPS. This clearly indicates that some patients do
not benefit from TIPS in this setting, and sometimes it is
The Patient with Poor Prognostic Indicators The
current consensus is to apply to all patients the same
treatment. However, it is plausible that patients with
poor prognostic indicators might benefit from a more
aggressive therapeutic approach ab initio. This was
recently explored in a randomized trial in which patients
with high PP (> 20 mm Hg) were randomized to receive
standard therapy or TIPS. Those who underwent early
TIPS had significantly less treatment failure and lower
mortality than patients undergoing standard therapy.65
However, the standard therapy used in the control arm
of this trial was only endoscopic therapy, which is not the
current standard of combination of vasoactive drugs and
endoscopic treatment.21 An ongoing multicenter study
will answer whether early TIPS (performed with covered
stents) is superior to combination therapy in high-risk
patients (ISRCTN58150114).
Gastric Varices Gastric varices develop in 20% of
patients with portal hypertension.100 They are the source
of 5 to 10% of all upper digestive bleeding episodes in
patients with cirrhosis. The risk of gastric variceal
bleeding is lower than that of esophageal variceal bleeding, but gastric variceal bleeding, in particular that from
fundal varices, tends to be more severe, to require more
transfusions, and to have a higher mortality rate.100
Fundal varices account for 1 to 3% of variceal bleeds.
The optimal treatment of gastric fundal varices
has not been determined, since there are only a few
RCTs and most data come from retrospective series
and case reports. The initial treatment is similar to
that of esophageal variceal bleeding, including the
administration of a vasoactive drug (either terlipressin,
somatostatin, or a somatostatin analogue) and general
management for hemodynamic stabilization and the
prevention of complications. However, the efficacy of
vasoactive drugs has not been assessed specifically.
Balloon tamponade, with the Linton-Nachlas tube,
has been used with limited success,101,102 but may serve
as a bridge to derivative treatments in massive bleedings.
Some endoscopic therapies are promising, but
quality information is scarce, and most studies include
both fundal varices and gastroesophageal varices. Sclerotherapy, variceal obturation with tissue adhesives
(‘‘glue injection’’), thrombin, elastic band ligation, and
ligation with large detachable snares have been reported.103 In most uncontrolled series, cyanoacrylate is
highly effective, on the order of 90%.104 Two recent
randomized trials compared banding ligation with
cyanoacrylate injection in patients with acute variceal
bleeding. In one trial cyanoacrylate injection was more
effective and safer than band ligation in the control of
acute bleeding, and was associated with less rebleeding.105 In another trial both treatments were equally
effective in the control acute of bleeding, but rebleeding
was more frequent in the ligation group.106 In another
RCT by Sarin and coworkers, cyanoacrylate was better
than alcohol injection in achieving initial hemostasis and
in achieving faster variceal obliteration.107 These trials
suggest that cyanoacrylate injection is the endoscopic
therapy of choice in acute bleeding from gastric varices.
This technique requires expertise, and is usually not
feasible during active bleeding.
TIPS is very effective in the treatment of bleeding
gastric varices, with more than a 90% success rate for
initial hemostasis and a low rebleeding rate.108,109 TIPS
is usually associated with the embolization of the collateral vessels that feed the varices. Derivative and devascularization surgery are also effective, but with limited
applicability in advanced cirrhosis.
The authors’ recommendation is to start with a
vasoactive drug. If bleeding is not controlled and if an
expert endoscopist is available, variceal obturation with
tissue adhesives should be attempted. In cases of massive
bleeding or after failure of previous therapies, TIPS (or
surgical shunt in Child-Pugh class A patients) is mandatory. In some patients, especially in those with massive
initial bleeding or in centers with reduced endoscopic
experience in the treatment of gastric varices, TIPS may
be used even before attempting endoscopic therapy.
Portal Hypertensive Gastropathy Portal hypertensive gastropathy (PHG) is a macroscopic finding of a
characteristic mosaic-like pattern of the gastric mucosa
(‘‘mild’’ PHG), red-point lesions, cherry red spots, and/
or black-brown spots (‘‘severe’’ PHG).110 These lesions,
however, are not entirely specific, that is, they can occur
in the absence of portal hypertension. In PHG there is
marked dilation of the vasculature of the gastric mucosa
and submucosa, together with an increased blood flow
and tendency to decreased acid secretion. PHG is unrelated to Helicobacter pylori infection. The overall prevalence of PHG in patients with cirrhosis strongly
correlates with the severity of the disease and ranges
between 11% and 80%.110 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 10 to
15% at 3 years. In acute bleeding, PHG b-adrenergic
blockers, somatostatin, octreotide, vassopressin, terlipressin, and estrogens have been proposed based on
their ability to decrease gastric perfusion in this condition.111–114 However, only one uncontrolled study so
far has evaluated one of these drugs (somatostatin) in
acute bleeding from PHG.115 Hemostasis was achieved
in all patients.
PREVENTION OF FIRST BLEEDING
Prophylactic Therapy: Who Benefits?
PATIENTS WITHOUT VARICES
The observation that nonselective b-blockers attenuated or delayed the development of collaterals in
experimental models of portal hypertension116
prompted studies to investigate whether these agents
could prevent the development of esophageal varices in
patients with cirrhosis. A recent study randomized 213
patients with cirrhosis and portal hypertension
but without varices to receive timolol (a nonselective
b-adrenergic blocker) or placebo for a median of
55 months.1 The primary end point was development
of esophageal varices or variceal hemorrhage. The rate
of development of the primary end point did not differ
between the two treatment groups (intention to treat).
The incidence of secondary end points (i.e, ascites,
encephalopathy, liver transplantation, or death) was
also not significantly different. Adverse events were
more frequent in the timolol group. Therefore, badrenergic blockers cannot be recommended for the
prevention of the development of esophageal varices.
Recent studies have shown that blockade of the vascular
endothelial growth factor signaling cascade is highly
effective in reducing the formation of collaterals in
experimental models,117,118 but no study has explored
this clinically. A different approach, which is easily
available, is to prevent the progression of cirrhosis
(i.e., abstinence in alcoholics, antivirals in viral cirrhosis, lifestyle change in nonalcoholic steatohepatitis,
corticosteroids in autoimmune hepatitis, phlebotomies
in hemochromatosis, copper chelators in Wilson’s
disease).
PATIENTS WITH VARICES
In the past, only patients with medium to large
varices were considered for prophylactic treatment of
variceal bleeding. This was because most studies with
b-adrenergic blockers were performed in patients with
medium to large varices, while the beneficial effects of bblockers are less clear in patients with small varices.60
However, the classification of varices according to their
size is very subjective. In fact, in the recent Baveno IV
consensus conference it was not possible to agree on a
definition of small and big varices.21 On the other hand,
it is well established that small varices with red signs or
in Child-Pugh class C patients have a bleeding risk
similar to that of big varices.14 Additionally, b-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.7 Therefore, the current recommendation is to extend prophylactic treatment to patients with small varices with red
signs or Child-Pugh C.21
13
14
2008
Screening for Varices: When and How
As previously discussed, the current consensus is that
every cirrhotic patient should be endoscopically screened
for varices at the time of diagnosis.7 In patients without
varices on initial endoscopy, a second (follow-up) evaluation should be performed after 2 to 3 years.21 Since
endoscopy is unpleasant for the patient, and screening in
all cirrhotic patients is a substantial burden, empirical bblocker therapy for all patients has been proposed. Two
studies suggest that this strategy is cost-effective,119,120
but a third suggested that empiric b-blockers are costeffective only in patients with decompensated cirrhosis.121 The lack of effectiveness of b-adrenergic blockers
to prevent the development of varices, and the high rate
of side effects observed in well-compensated patients,1
call into question the use of b-adrenergic blockers
without screening.
Treatments for the Prevention of First Bleeding:
b-Adrenergic Blockers versus EBL
Nonselective b-adrenergic blockers (propranolol or
nadolol) have been shown to reduce the risk of first
variceal bleeding (from 24 to 15% after a median
follow-up of 2 years).60 Mortality was also reduced
(from 27 to 23%) though this did not achieve statistical
significance.60 It is important to note that b-blockers
are among the safest and least expensive drugs in
Europe. However, about 25% of cirrhotic patients
with medium/large esophageal varices may have either
contraindications for the administration of nonselective
b-blockers or cannot tolerate these drugs, and the
degree of protection afforded (40% relative risk
reduction) is far from ideal, which has stimulated the
search for alternative treatments.
EBL is effective in preventing the first variceal
bleeding in patients with medium to large varices.122
Sixteen trials have compared EBL with b-adrenergic
blockers as a first-line option for primary prophylaxis of
variceal bleeding.123–138 The meta-analysis of these trials
shows an advantage of EBL over b-adrenergic blockers
in terms of prevention of first bleeding, without differences in mortality (Fig. 5). Six of these trials are only
available in abstract, which makes it difficult to evaluate
their quality, and most trials were underpowered or lack
any sample size calculation (11 out of 16 included fewer
than 100 patients). Four of the trials were prematurely
stopped after an interim analysis, due to futility in three
cases125,131,138 or to an apparently significant benefit
of banding in a small study.130 When meta-analysis
is restricted to published studies with a quality score
above 5 (out of 10), there is no significant benefit from
EBL.
These data have led to considerable controversy
over whether ß-blockers should remain the first treatment option to prevent first variceal bleeding, since in
addition to the higher efficacy of banding ligation,
adverse events requiring treatment discontinuation
were significantly more frequent in patients treated
with nonselective b-blockers.139 However, the type
and severity of side effects was different between the
two therapies.140 Indeed, most side effects related to
b-blockers (hypotension, tiredness, breathlessness, poor
memory, insomnia) were subjective and were easily
managed by adjusting the dose or discontinuing bblockers, did not require hospital admission, and resulted
in no fatalities. In contrast, side effects related to EBL
included 12 bleeding episodes and 1 esophageal perforation. In most cases, these complications required
hospitalization and blood transfusion and resulted in 3
deaths.125,138 Further, because of the short duration of
follow-up in most of these studies, the long-term safety
and benefits of prophylactic EBL are still uncertain.
On the contrary, long-term safety and efficacy of
nonselective b-adrenergic blockers are well established.141,142 Bleeding episodes after discontinuing
b-blockers because of side effects have also been considered as an argument against their use as first choice.
However, most of these bleedings occurred months or
years after b-blockers were withdrawn, suggesting that
if an alternative therapy, such as EBL, had been offered
to these patients, some of these bleeding episodes could
have been prevented. The cost-effectiveness of EBL
versus ß-blockers for primary prophylaxis has been
compared in three decision-analysis studies. Different
assumptions on the incidence of variceal bleeding,
quality of life with each treatment, mortality, or other
portal hypertensive complications led to conflicting
conclusions.119,121,143
The recommendation made at the 2005 Baveno
consensus conference is that nonselective b-blockers
should be considered as first-choice treatment to prevent
first variceal bleeding, while EBL should be offered to
patients with medium/large varices and contraindications or intolerance to b-blockers (Table 3).21 Even in
this case, a recent trial shed some doubts on the use of
EBL. In that trial EBL was compared with no treatment
in patients with contraindications to b-blockers. The
trial was prematurely stopped due to a high rate (12%) of
iatrogenic bleeding in the band ligation group.144 However, the early termination of the trial frustrated the
possibility of obtaining clear-cut evidence to support a
recommendation.
The combination of EBL plus b-adrenergic
blockers appears to offer no benefit in terms of prevention of first bleeding when compared with EBL alone.145
There is a lower rate of recurrence of varices in patients
treated with EBL plus propranolol but at the expense of
more side effects. Probably more studies would be
required, although these are unlikely to be performed
due to the very large number of patients that would be
needed.
Figure 5 Prevention of first variceal bleeding. Meta-analysis (random effects model) of randomized controlled trials
comparing endoscopic band ligation with b-adrenergic blockers in the prevention of first variceal bleeding. (A) Bleeding. (B)
Mortality. EBL, endoscopic band ligation; RR, relative risk; CI, confidence interval.
Unanswered Issues
HVPG MONITORING
Three longitudinal studies have demonstrated that a
sufficient HVPG decrease (to 12 mm Hg or below or
of more than 20% from baseline) is associated with an
effective protection from first variceal bleeding.12,18,142
This leads to the question of whether HVPG measurements should be used to monitor PP response to drug
treatment in clinical practice. Two simulation analyses
have yielded conflicting results, one suggesting that
HVPG monitoring might be cost-effective in primary
prophylaxis,146 and the other arriving at the opposite
conclusion.147 The main problem is that the assumptions
of these analyses (i.e., how to manage nonresponders to
medical treatment) have never been tested in randomized controlled trials. A recent study of HVPG-guided
therapy suggested that the shift of nonresponders from
b-blockers to EBL does not improve the outcome.148
The issue will remain hypothetical until HVPG-guided
therapy is proven to be better than empirical approaches
in randomized controlled trials.
15
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2008
Table 3 Prophylaxis of First Variceal Bleeding:
Recommendations
including a large number of patients failed to confirm
these results.152
Patients without varices should be screened endoscopically
for the appearance of varices every 2 to 3 years.
Patients with moderate/large varices should be treated with a
nonselective b-blocker if there are no contraindications.
Patients with small varices with red signs or with advanced
liver failure (Child-Pugh C) are at similar risk of bleeding as
those with moderate/large varices and should be considered
for preventive therapy.
Patients with moderate/large varices with contraindications to
or who cannot tolerate b-blockers should undergo endoscopic
band ligation; band ligation might be used as the first choice in
patients with large varices depending on patient’s preferences
and local resources.
If no bleeding occurs treatment should be maintained for life
(unless the liver disease improves and significant portal
hypertension disappears).
THE COMBINATION OF b-ADRENERGIC BLOCKERS WITH
NITRATES
The addition of ISMN has been shown to significantly
increase the long-term HVPG response to b-adrenergic blockers.149 However, it is less clear whether
the greater effect of this combination on PP translates
into a greater clinical efficacy in primary prophylaxis.
An open trial comparing nadolol to nadolol þ isosorbide mononitrate demonstrated a significantly lower rate of first bleeding in the combination
group, without survival advantage.150,151 However,
a subsequent double-blind, placebo-controlled study
ENDOSCOPIC TREATMENT: HOW FREQUENT, HOW TO
MONITOR THE TREATMENT
There is no agreement on how frequently the varices
should be ligated in the initial course of eradication.
Some authors wait a minimum of 1 month between
banding procedures,130 while others perform EBL on a
weekly basis.125 Reported frequency of complications
with the former strategy was lower than with the latter.
A recent trial evaluated the effectiveness and complications of EBL performed every 2 weeks compared withevery 2 months. This trial included patients with and
without previous bleeding, though most patients were
treated for primary prophylaxis.153 The 2-month interval
scheme obtained a higher total eradication rate and a
lower recurrence rate. No patient in either group developed variceal bleeding. Thus, although admittedly weak,
current evidence favors monthly intervals. Follow-up
endoscopies should be performed every 6 months and
varices should be re-eradicated upon recurrence. This is
in marked contrast to prophylaxis with b-blockers, in
which no follow-up endoscopies are needed.
PREVENTION OF RECURRENT BLEEDING
FROM ESOPHAGEAL VARICES
Patients surviving a first episode of variceal bleeding have
a high risk of recurrent bleeding, of over 60% within
1 year from the first bleeding. Because of this, all patients
surviving a variceal bleeding should receive active treatments for the prevention of rebleeding21 (Fig. 6, Table 4).
Figure 6 Reported variceal rebleeding rate with different treatment options. Constructed from data of randomized clinical
trials for secondary prevention of variceal rebleeding. EIS, endoscopic injection sclerotherapy; BB, beta-blockers; EBL,
endoscopic band ligation; ISMN, isosorbide-5-mononitrate; TIPS, transjugular intrahepatic portal-systemic shunts; DSRS, distal
splenorenal shunt; HVPG, hepatic venous pressure gradient. (Based on data from Bosch J, Garcia-Pagan J. Prevention of
variceal rebleeding. Lancet 2003;361:952–954.)
Table 4 Prevention of Variceal Rebleeding:
Recommendations
All patients surviving a bleeding episode should be treated
to prevent recurrent bleeding; in patients who bled and were
not receiving b-blockers, either b-blockers ISMN, band
ligation, or both can be used.
Patients who bled while on b-blocker or under prophylactic
EBL should be treated with the combination of EBL plus
b-blockers.
Patients who are intolerant to or who have contraindications
between the treatments in preventing rebleeding or in
mortality.
Compared with TIPS, the combination of ISMN
and propranolol is less effective for the prevention of
rebleeding but it is associated with significantly less
encephalopathy, similar mortality, and much lower
cost.162
Treatment dosage and schedules for propranolol,
nadolol, and ISMN are the same as for the prevention of
first bleeding.
to b-blockers should be treated with EBL.
The efficacy of TIPS in the prevention of recurrent bleeding
from esophageal varices is not different from that of shunt
surgery (distal splenorenal shunt or 8-mm Hg graft shunt),
especially since the introduction of PTFE-covered stents.
Failures of medical therapy are preferably managed with
PTFE-TIPS; this is the only option in poor surgical candidates.
Patients who survive a bleeding episode and have advanced
liver failure (Child-Pugh score > 8 or MELD > 16) should be
considered for liver transplantation.
ISMN, isosorbide-5-mononitrate; EBL, endoscopic band ligation;
TIPS, transjugular intrahepatic portal-systemic shunt; PTFE, polytetrafluoroethylene; MELD, model for end-stage liver disease.
Pharmacological Treatment
The efficacy of nonselective b-blockers in the prevention
of variceal rebleeding has been proven in many RCTs,
and these drugs are now widely accepted as the first-line
pharmacological therapy in this setting21. Several metaanalyses have consistently found a marked benefit from
b-blockers showing a reduction in rebleeding rate from
63% in controls to 42% in treated patients.60 Mortality
was significantly reduced, from 27 to 20%60 and mortality from bleeding was also significantly reduced.154 Betablockers have been compared with endoscopic variceal
sclerotherapy in the prevention of rebleeding. No significant differences were found either for rebleeding or
for mortality but side effects were significantly less
frequent and severe with b-blockers.60
The combined administration of propranolol or
nadolol plus ISMN was introduced after demonstrating
that ISMN enhanced the PP-reducing effect of nonselective b-blockers.149 There is insufficient information
on whether this translates into a clinical advantage, since
there are only two studies of ISMN associated with
propranolol155 or nadolol156 versus the corresponding
b-blocker alone, in the prevention of rebleeding. One
of these studies showed significant benefit, but not the
second (which is still available only in abstract form).156
However, the association of ISMN with propranolol or
nadolol has been found to be superior to endoscopic
sclerotherapy in one study.157 In addition, the association of propranolol/nadolol and ISMN has been compared with EBL in four studies.158–161 Meta-analysis of
these four studies has shown no significant differences
Endoscopic Treatment
Endoscopic injection sclerotherapy of esophageal varices
significantly reduces both the rebleeding and death
risk. It takes four to six endoscopic sessions to eradicate
varices, but recurrence of varices occurs in nearly 40% of
patients within 1 year from eradication. This requires
further endoscopic sessions to maintain eradication. The
most serious side effects of therapy are dysphagia,
esophageal stenosis, and bleeding from esophageal ulcers, which may account for as much as 14% of all the
rebleeding episodes. As noted above, sclerotherapy
has no advantage over drug therapy and causes more
frequent and severe side effects.
Endoscopic banding ligation has been proven
superior to sclerotherapy.140 Complications are significantly less frequent and severe with banding ligation.
Therefore, banding ligation should be preferred to
sclerotherapy.21 Surprisingly, despite decreasing rebleeding rates, endoscopic ligation does not significantly
improve survival compared with sclerotherapy. Although
variceal eradication is achieved with a lower number of
EBL sessions than with sclerotherapy, there is evidence
that it is associated with higher recurrence of varices.140
Combined Endoscopic Treatment
In the approach using banding ligation combined with
sclerotherapy, sclerotherapy has been added (either simultaneously or after the reduction of variceal size to small)
to EBL and compared with band ligation alone, yielding
contrasting results. The meta-analysis of these studies
does not show any benefit either for rebleeding or for
mortality, and importantly, it shows a trend toward
an increasing complication rate with combination endoscopic therapy.
Combined Endoscopic and Pharmacological
Treatment
The association of injection sclerotherapy and b-blockers has been compared with either sclerotherapy or
b-blockers alone. The meta-analysis of the RCTs comparing combination therapy with sclerotherapy alone
showed a significant reduction of the rebleeding
17
18
2008
risk with combination therapy, but no differences in
mortality.3 Also, when compared with b-blockers alone,
combination therapy significantly reduced the rebleeding risk without advantage for survival.60
Two RCTs have shown that the combination of
banding ligation plus b-blockers is superior to banding
ligation alone in terms of recurrence of varices and
recurrence of bleeding.163,164 In addition, in one RCT,
adding band ligation to nadolol plus ISMN was shown
to be superior to nadolol þ ISMN alone in preventing
variceal rebleeding. However, no significant differences
were observed when considering rebleeding episodes of
any cause. This was due to a greater number of ulcerrelated bleeding episodes in the treatment arm including
banding.165 All together, these results emphasize that
the possible greater clinical efficacy of the combination
of endoscopic plus drug treatment in the prevention of
rebleeding should be further evaluated. However, until
then the recommendation is to use the combination in
patients who bled under either treatment alone. In these
patients, the substitution of the failing treatment with
the other should not be preferred to their combination.
TIPS
TIPS has been compared with sclerotherapy and
with banding ligation showing almost consistently that
TIPS is superior to either endoscopic therapy for the
prevention of rebleeding. Similarly, TIPS has also been
shown to be superior to the combination of ISMN and
propranolol.162 Not surprisingly, this impressive efficacy
in preventing recurrent bleeding is associated with a
marked increase in the risk of encephalopathy without
reducing either overall mortality or mortality from
bleeding.
TIPS has been compared with surgical shunts in
two RCTs.166 In the first study, TIPS was compared
with 8-mm portocaval H-graft shunt.166,167 A significantly lower rebleeding rate was found with the surgical
shunt. Significantly more patients required liver transplant in the TIPS group than in the surgical shunt group.
There was no difference in mortality. The composite end
point of ‘‘failures’’ which included rebleeding, shunt
thrombosis, deaths, and need for transplant, was significantly higher for the TIPS. In the second trial TIPS was
compared with the distal splenorenal shunt (DSRS) in
Child-Pugh class A and B patients.167 No significant
differences in rebleeding rate (5.5% in the DSRS group,
and 9% in the TIPS group), incidence of hepatic
encephalopathy, liver transplantation, or mortality was
found. However, to obtain these results the reintervention rate was significantly higher in the TIPS group
(82%) than in the DSRS group (11%). However, new
polytetrafluoroethylene (PTFE)-covered stents have
solved one of the major drawbacks of TIPS’ use of
bare stents, that is, its high rate of occlusion or dysfunc-
tion. Indeed, a multicenter RCT reported much lower
obstruction and reintervention rates with the use of
PTFE stents, which was associated with lower rates of
recurrent bleeding or ascites without an increase in the
incidence of encephalopathy, than with the use of bare
stents.168 These results suggest that the small disadvantage of TIPS versus surgical shunt would be overcome by
the use of PTFE-covered stents.
HVPG-Guided Therapy in the Prevention of
Rebleeding
Pharmacological (or spontaneous) reduction of HVPG
to < 12 mm Hg or by 20% of the baseline value
(HVPG responders) markedly decreases the risk of
rebleeding and also reduces mortality.169 Indeed,
achieving such a hemodynamic response is associated
with a rebleeding risk that is even lower than that
achieved using surgical shunts or TIPS170 (Fig. 7). As
a consequence, to add further treatment (i.e., band
ligation) to these patients is likely to not enhance
efficacy but to increase the side effects. On the other
hand, it is still unclear whether patients with an
insufficient hemodynamic response to pharmacological
therapy would benefit from adding other drugs or
alternative treatments.
As previously discussed, a decision analysis does
not clearly suggest that HVPG-guided therapy is costeffective in the primary prevention of variceal bleeding.
However, probably because of the higher risk of variceal
hemorrhage in secondary prophylaxis, a recent study
concluded that the use of nonselective b-blockers þ long-acting nitrates offering EBL to HVPG nonresponders was cost-effective and only marginally more
expensive than EBL or pharmacological treatment without HVPG monitoring.171 However, decision analysis
models are limited by the many assumptions on which
these are based. Because of these, the value of HVPGguided therapy must be demonstrated in randomized
clinical studies. A first attempt was done by Bureau and
colleagues148 In this study, HVPG nonresponders to
b-blockers were given ISMN and if their condition
remained unchanged, they were shifted to EBL.
Although the study included low numbers, it suggested
that band ligation is not a good alternative in HVPG
nonresponders. Preliminary data from a Spanish multicenter RCT comparing nadolol þ ISMN with nadolol þ ISMN þ EBL165 found no significant differences
in rebleeding rates in HVPG nonresponders treated with
drugs alone or with drugs þ EBL, suggesting that adding EBL may not be the best alternative to reduce
rebleeding in HVPG nonresponders. It is therefore
possible that more effective and aggressive therapies
are required to reduce the high rebleeding tendency of
HVPG nonresponders (46 to 65% in a recent survey170).
The recent study by Gonzalez et al found a 19%
Figure 7 Meta-analysis of the randomized clinical trial (RCTs) comparing b-blockers þ isosorbide-5-mononitrate (ISMN) with
endoscopic band ligation (EBL) of esophageal varices to prevent recurrent variceal bleeding and mortality. Each RCT is identified
by the name of the first author and the year of publication. Squares indicate the odds ratio (OR) with the two treatments for each
RCT. Horizontal bars denote the 95% confidence interval (CI) of the OR. The vertical line represents the line of identity of effect
of the two treatments. The diamonds represent 95% CIs of the pooled OR.
rebleeding rate in the HVPG nonresponders that were
shifted to receive TIPS, suggesting that this might be an
option.172 Unfortunately, the study included a small
number of patients and had no control group. Therefore,
investigators should continue to study HVPG-guided
therapy in order to be able to make clear recommendations.
PHG despite pharmacological therapy may benefit from
endoscopic ablation, either by argon plasma coagulation,
neodymium:yttrium-aluminum-garnet (Nd:YAG) laser,
or heater probe. If this is not feasible or fails, TIPS may
be considered as an alternative therapy. PHG reverses
after liver transplantation.
ACKNOWLEDGMENTS
Treatment of Gastric Varices
The optimal treatment to prevent gastric (fundal) variceal bleeding is not well defined, due to the relatively low
incidence of this condition. In clinical practice, nonselective b-blockers or the tissue adhesive isobutyl-2cyanoacrylate (bucrylate) are used as first line therapy.
PTFE-TIPS or shunt surgery is recommended in
failures.
Treatment of PHG
Prevention of recurrent bleeding from PHG should be
based on nonselective b-blockers, at the same dosage as
for treating esophageal varices.173 Adequate iron supplementation may be useful to prevent or correct chronic
iron-deficient anemia in patients with severe PHG.173
Rare patients who have repeated severe bleeding from
We thank Ms. Clara Esteva for expert secretarial support. This study was supported in part by grants from the
Ministerio de Educacioń y Ciencia (SAF-04/04783),
and from Instituto de Salud Carlos III (FIS 06/0623
and 05/0519).
ABBREVIATIONS
CDUS color Doppler ultrasound
CSPH clinically significant portal hypertension
CT
computed tomography
DSRS
distal splenorenal shunt
EBL
endoscopic band ligation
HVPG hepatic venous pressure gradient
ISMN isosorbide-5-mononitrate
IVC
inferior vena cava
MRI
magnetic resonance imaging
19
20
NO
PHG
PP
PPG
PTFE
RCT
TIPS
US
2008
nitric oxide
portal hypertensive gastropathy
portal pressure
portal pressure gradient
polytetrafluoroethylene
randomized clinical trial
transjugular intrahepatic portal-systemic
shunts
ultrasound
15.
16.
17.
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Portal Hypertension and Gastrointestinal Bleeding

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