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Received: 12 October 2016    Accepted: 19 October 2016

DOI: 10.1111/liv.13277

REVIEW ARTICLE

Prevention and treatment of variceal haemorrhage in 2017

Felix Brunner1 | Annalisa Berzigotti1 | Jaime Bosch1,2

1
Swiss Liver Center, Hepatology, University
Clinic for Visceral Surgery and Abstract
Medicine, Inselspital, Bern University Variceal haemorrhage is a major complication of portal hypertension that still causes
Hospital, University of Bern, Bern,
Switzerland high mortality in patients with cirrhosis. Improved knowledge of the pathophysiology
2
Hepatic Hemodynamic Laboratory, Hospital of portal hypertension has recently led to a more comprehensive approach to prevent
Clinic-IDIBAPS and CIBEREHD, University
all the complications of this condition. Thus, optimal treatment of portal hypertension
of Barcelona, Barcelona, Spain
requires a strategy that takes into account the clinical stage of the disease and all the
Funding Information
major variables that affect the risk of progression to the next stage and death. In pa-
None.
tients with compensated liver disease, the correction of factors influencing the pro-
Correspondence
Prof. Jaime Bosch, MD, PhD, FRCP, Hepatic gression of fibrosis, in particular aetiologic factors, is now feasible in many cases and
Hemodynamic Laboratory, Hospital Clinic, should be achieved to prevent the development or progression of gastroesophageal
IDIBAPS and CIBEREHD, University of
Barcelona, Barcelona, Spain. varices and hepatic decompensation. Once gastroesophageal varices have developed,
Email: jbosch@clinic.ub.es non-­selective beta-­blockers remain the cornerstone of therapy. Carvedilol provides a
Handling Editor: Francesco Negro greater decrease in portal pressure and is currently indicated as a first-­choice therapy
for primary prophylaxis. The treatment of acute variceal haemorrhage includes a com-
bination of vasoactive drugs, antibiotics and endoscopic variceal band ligation. In high-­
risk patients, the early use of transjugular intrahepatic portosystemic shunt (TIPS)
lowers the risk of re-­bleeding and improves survival. Transjugular intrahepatic porto-
systemic shunt is the choice for uncontrolled variceal bleeding; a self-­expandable
metal stent or balloon tamponade can be used as a bridging measure. The combination
of non-­selective beta-­blockers and endoscopic variceal band ligation reduces the risk
of recurrent variceal bleeding and improves survival. In these cases, statins seem to
further improve survival. Transjugular intrahepatic portosystemic shunt is indicated in
patients who rebleed during secondary prophylaxis.

KEYWORDS
cirrhosis, portal hypertension, variceal bleeding, varices

1 | INTRODUCTION bleeding from gastroesophageal varices (GEVs) and portal hyper-


tensive ­gastropathy, a scites, ­spontaneous bacterial peritonitis
Portal hypertension is the most severe and frequent compli- (SBP), ­hepatorenal ­syndrome (HRS), hepatic encephalopathy (HE),
cation of chronic liver disease. This complication is the cause hepatopulmonary and porto-­pulmonary syndrome, bacteremia and
of most of the severe clinical symptoms of cirrhosis, such as hypersplenism.

Abbreviations: (c)ACLD, (compensated) advanced chronic liver disease; ACE, angiotensin-converting enzyme; BRTO, balloon-occluded retrograde transvenous obliteration; CSPH, clinically
significant portal hypertension; CT, computer tomography; EIS, endoscopic injection sclerotherapy; e-NOS, endothelial NO synthase; EV, oesophageal varices; EVL, endoscopic variceal band
ligation; GEV, gastroesophageal varices; GOV1+2, gastroesophageal varices type 1+2; HE, hepatic encephalopathy; HRS, hepatorenal syndrome; HSC, hepatic stellate cells; HVPG, hepatic
venous pressure gradient; ICU, intensive care unit; IGV1+2, isolated gastric varices type 1 +2; ISMN, isosorbide-5-mononitrate; LSM, liver stiffness measurements; MRI, magnetic resonance
imaging; NASH, non-alcoholic steatohepatitis; NO, nitric oxide; NSBB, non-selective beta-blockers; OCA, obeticholic acid; PPG, portal pressure gradient; PTFE, polytetrafluoroethylene; RCT,
randomized controlled trial; SBP, spontaneous bacterial peritonitis; SEC, sinusoidal endothelial cells; TE, transient elastography; TIPS, transjugular intrahepatic portosystemic shunt; VEGF,
vascular endothelial growth factor.

104  |  © 2017 John Wiley & Sons A/S.


wileyonlinelibrary.com/journal/liv Liver International 2017; 37(Suppl. 1): 104–115
Published by John Wiley & Sons Ltd
BRUNNER et al. |
      105

Portal hypertension is defined as an increased portosystemic pres-


sure gradient (difference between pressures in the portal vein and the
inferior vena cava), which can be evaluated clinically by measuring the Key points
hepatic venous pressure gradient (HVPG) through hepatic vein cath- • Treatment of portal hypertension must take into account
1
eterization. This review will only focus on portal hypertension due the clinical stage of chronic advanced liver disease.
to chronic liver disease (sinusoidal portal hypertension), which is the • Non-selective beta-blockers remain the cornerstone of
leading aetiology, followed by schistosomiasis (in developing coun- the prevention of variceal bleeding, re-bleeding and other
tries), portal and splenic vein thrombosis, Budd-­Chiari syndrome and complications of portal hypertension, and they improve
other less frequent conditions due to presinusoidal or post-­sinusoidal survival in patients with optimal hemodynamic response.
block. • Major advances include the use of carvedilol for primary
Portal hypertension is defined by a HVPG>5 mm Hg, but the risk prophylaxis of variceal bleeding and the use of statins
of developing GEV and the clinical complications of decompensated combined with NSBB and EVL to reduce mortality in pa-
chronic liver disease (e.g. ascites, variceal bleeding and overt HE) are tients who have bled from variceal rupture.
2
only present when it reaches ≥10 mm Hg. Thus, HVPG ≥10 mm Hg is • TIPS is now used early after a first episode of bleeding in
called “clinically significant portal hypertension” (CSPH). high-risk patients, as a life-saving procedure in massive
At diagnosis, up to half of the patients with compensated cirrhosis bleeding, and to prevent rebleeding in patients not re-
have developed GEV. This is even more frequent in patients with se- sponding to standard therapy (NSBB + EVL).
3
verely impaired liver function (Child-­Pugh class B/C). GEVs develop
with an annual incidence of 5%-­9% in patients without varices at diag-
nosis.4,5 The rate of progression from small to large varices is similar. increases if it is combined with other data suggesting portal hyperten-
Prospective studies in the 1980s showed that the risk of first variceal sion, such as a reduced platelet count and increased spleen size in
bleed increases with impairment of liver function, size of varices and the so-­called LSPS index.11 The non-­invasive diagnosis of CSPH in a
presence of red colour signs over the varices (red wales, red spots, dif- patient without varices can also be made by detecting portal-­systemic
fuse redness) with an annual risk of approximately 12% (5% for small collaterals with imaging techniques (ultrasound, CT or MRI). The lat-
varices and 15% for large varices).6,7 Bleeding from ruptured GEV is a est Baveno consensus conference recommends that patients with an
major medical emergency, with a 6-­week mortality of approximately LSM value ≥20 kPa and/or a decreased platelet count (<150 G/L) un-
15% especially patients with poor liver function (Child-­Pugh C). In dergo endoscopic screening for the presence of GEV, while patients
many cases, death does not occur due to bleeding, but to infections, with both LSM<20 kPa and platelet count >150 G/L can safely skip
HRS and liver failure because of the bleeding episode. In the last three endoscopy due to the low risk of having varices requiring treatment.10
decades, improvement in evidence-­based-­guided treatment of portal Based on the natural history of the disease, ACLD/cirrhosis can
hypertension and management of acute bleeding episodes has cut the be classified into five stages according to the presence or absence of
mortality due to GEV bleeding in half.8 complications (Table 1).12,13

2 |  STAGES OF CIRRHOSIS AND 3 | PATHOPHYSIOLOGY OF PORTAL


PORTAL HYPERTENSION: FROM HYPERTENSION AND ITS CHANGE WITH
FIBROSIS TO CLINICALLY SIGNIFICANT DISEASE PROGRESSION
PORTAL HYPERTENSION
The pathophysiology of portal hypertension is essentially
In chronic liver disease, fibrosis progresses leading to cirrhosis and based on applying Ohm’s law to hemodynamics: Pressure
continues to worsen as long as the aetiologic factor is present. In daily Gradient=Resistance × Flow. Thus, portal hypertension may be
practice, liver fibrosis is usually measured non-­invasively by determin- due to increased resistance to portal blood flow, increased blood
ing liver stiffness to assess the degree of fibrosis without a biopsy.9 flow through the portal-­collateral system or a combination of both
Since cirrhosis is an anatomical diagnosis requiring a liver biopsy, the (Figure 1). In ACLD, increased resistance to portal blood flow occurs
term “compensated advanced chronic liver disease (cACLD)” has been not only because of the obvious architectural changes in the liver vas-
10
suggested rather than cirrhosis. In asymptomatic compensated pa- culature (fibrosis, nodules, angiogenesis and sinusoidal remodelling)
tients, values below 10 kPa on liver stiffness measurements (LSMs) by but also due to dynamic changes in the sinusoids. Once they have
transient elastography (TE) exclude cACLD, while values between 10 been activated through inflammatory signalling or other stimuli, the
and 15 kPa suggest sACLD but are not diagnostic, and correspond to adjacent hepatic stellate cells (HSCs), which reside in the space of
a “grey zone,” and cACLD is very likely in patients with values above Disse (virtual space between hepatocytes and sinusoidal endothelial
15 kPa.10 Liver stiffness measurements have also been found to corre- cells [SECs]), begin to deposit extracellular matrix proteins and col-
late with the presence of CSPH (values >13 suggest cirrhosis, and >20 lagen. Microthrombi in small hepatic veins aggravate the structural
are almost pathognomonic). The diagnostic accuracy of elastography component by causing hepatocyte drop-­out and areas of parenchymal
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106       BRUNNER et al.

T A B L E   1   Stages of advanced chronic liver disease

Stage 1a Stage 1b Stage 2 Stage 3 Stage 4 Stage 5

Characteristics Compensated Compensated Compensated Variceal bleeding First non-­bleeding Any second
without without with varices without any decompensation decompensating
varices varices other (e.g. ascites, HE, event
complication jaundice)
No CSPH CSPH CSPH CSPH CSPH CSPH
1-­y mortality 1.5% 2% 10% 21% 87% 5-­y-­mortality
Complications (annual 7% GEV 6.6% Ascites 21% Progress to 10% Progress to
incidence) 4% Ascites 4% GEV stage 4 stage 5
bleeding

CSPH, clinically significant portal hypertension (HVPG>10 mm Hg); GEV, gastroesophageal varices; HE, hepatic encephalopathy.

extinction. This structural component is thought to account for about Collateral formation is not only caused by increased portal
70% of the increased hepatic resistance to portal blood flow. pressure, but requires active angiogenesis, driven by vascular en-
The remaining 30% is a dynamic component including active con- dothelial growth factor (VEGF). VEGF not only activates—among
traction of activated HSC wrapped around sinusoids, myofibroblasts others—the eNOS signalling pathway, but also promotes the forma-
in the portal tracts, and vascular smooth muscle cells in the hepatic tion of portosystemic collaterals and GEV. Physiologically, porto-
vasculature. In response to chronic liver damage, the SECs lose their systemic collaterals are shunts between the portal and the systemic
fenestrae, which normally allow passive transport of macromolecules circulation that contribute to the hyperkinetic systemic circulation
from the sinusoidal lumen to hepatocytes. A basement membrane de- and hepatic encephalopathy as well as impaired metabolism of
velops along the sinusoidal surface of liver SEC, leading to capillar- drugs and toxins.
ization of sinusoids that exhibit endothelial dysfunction. Endothelial
dysfunction is characterized by impaired release of vasodilatory agents,
4 | Current treatments for portal hypertension
mainly nitric oxide (NO) by the endothelial NO synthase (e-­NOS). In a
(Table 2)
setting of increased vasoconstrictor drive due to increased endothelin
production, activated renin-­angiotensin and adrenergic systems and
4.1 | Non-­selective beta-­blockers (NSBBs)
enhanced release of thromboxane A2, the lack of sufficient NO results
remain the cornerstone of prevention of bleeding
in hepatic vasoconstriction further increasing hepatic resistance and
worsening portal hypertension (Figure 1).14 Traditional NSBB have been used for more than 30 years
More advanced portal hypertension with the presence of portal-­ Standard NSBBs (propranolol, nadolol and timolol) decrease portal
systemic collaterals (stage 2) is accompanied by splanchnic vasodila- pressure by reducing portal-­collateral blood flow through reduction
tion, increased inflow of blood into the splanchnic organs draining into of the cardiac index (via beta1-­receptor blockade) and splanchnic
the portal venous system and increased portal-­collateral blood flow. vasoconstriction (via beta2-­adrenoceptor blockade).5,15 Therefore,
Vasodilation is mediated by increased release of vasodilators, includ- hyperkinetic circulation is necessary for them to act. For more than
ing NO, carbon monoxide, endogenous cannabinoids and vasodilatory 30 years, NSBBs have been shown to effectively prevent a first GEV
peptides of splanchnic origin such as glucagon. This is the opposite of bleed and recurrence of GEV bleeding, as well as to lower bleeding-­
the intrahepatic circulation (which exhibits vasoconstriction) and rep- associated mortality.16,17 Moreover, NSBBs increase intestinal transit
resents an adaptive homeostatic response to maintain portal perfusion time, reduce bacterial translocation and lower the risk of spontaneous
of the liver, which is reduced by the development of prehepatic and bacterial peritonitis.18 To effectively prevent variceal bleeding, NSBB
intra-­hepatic portal-­systemic shunts. However, the increased portal-­ should reduce the HVPG to 12 mm Hg or below (optimal response) or
collateral blood flow further worsens portal hypertension, accelerating at least by 20% of its baseline value (good hemodynamic response).
the development of collaterals causing further splanchnic vasodilation, However, a long-­term satisfactory hemodynamic response is only ob-
creating a vicious cycle. Severe splanchnic vasodilation may result in tained in 33%-­50% of patients with NSBB. In non-­responders, addi-
peripheral resistance and hypotension and “effective hypovolaemia,” tion of low doses of an NO-­donor such as isosorbide-­5-­mononitrate
causing activation of endogenous vasoactive systems, which trigger (ISMN) causes an additional decrease in portal pressure, while in-
plasma volume expansion (Figure 1). This expanded plasma volume creasing side effects.19,20 However, the fixed combination of NSBB
and the additional blood volume returning from the portal-­systemic and ISMN is not clearly better than NSBB alone in preventing a first
collaterals to the right atrium promotes increased cardiac output and episode of GEV bleeding, but in an à la carte HVPG-­guided approach,
a full-­blown hyperkinetic syndrome. In stages 3 and 4, vasodilation is the addition of ISMN has been shown to rescue about one third of
so intense that clinical sodium retention is triggered and located in the non-­responders to NSBB.20,21 The recommended dosages of NSBB
peritoneal cavity in the form of ascites (Figure 1). and most frequent side effects are listed in Table 2.
BRUNNER et al. |
      107

is sustained for several hours.25 Due to its long biological activity,


terlipressin can be administered every 4 hours as repeat intravenous
injections, although if it is given as a continuous infusion the total
dose may be decrease. Due to the intravenous administration of this
agent, it is only used for short periods, which in practice is limited to
the treatment of acute variceal bleeding (2-­5 days) or type-­I hepato-
renal syndrome (1-­2 weeks). Because of the potential ischaemic and
arrhythmic complications, terlipressin should not be used in patients
with a history of coronary, cerebrovascular, peripheral or visceral ar-
terial diseases. Also, it should be used with caution in elderly and/or
hypertensive patients.

4.3 | Somatostatin and long-­acting somatostatin


analogues are also potent splanchnic vasoconstrictors
Somatostatin is also an effective splanchnic vasoconstrictor that
effectively decreases portal pressure through the inhibition of
glucagon and other vasoactive peptides and the facilitation of adr-
energic vasoconstriction.25,26 Because of its very short half-­life
(1-­3 minutes), it should be administered in a continuous intravenous
infusion. Dose-­response studies have shown that to significantly
F I G U R E   1   Pathophysiology of portal hypertension and potential decrease both HVPG and portal-­collateral (azygos) blood flow, a
targets for drug therapy dose of 500 μg/hour is required.27 Long-­acting analogues (octreo-
tide, vapreotide, and lanreotide) have been developed to overcome
the short half-­life of somatostatin. After a bolus of octreotide the,
HVPG markedly decreases in a manner similar to somatostatin
Carvedilol is more effective than propranolol/nadolol (around 50%), but this effect is short and decreases with repeated
In addition to its capacity to block beta1-­ and beta2-­receptors, the administration. The decrease in the HVPG is not maintained by a
NSBB carvedilol has an intrinsic anti-­α-­adrenergic activity and the po- continuous intravenous infusion, but limits the postprandial increase
tential to release NO. This is why it is more effective in lowering portal in portal pressure in patients with portal hypertension. However,
hypertension than propranolol/nadolol after acute or chronic adminis- this only partially explains why octreotide successfully controls GEV
tration (in a face-­to face randomized comparison, the mean HVPG de- bleeding.28
22
crease was 22.2% vs 15.6% respectively). Moreover, more than half
(56%) of non-­responders to standard NSBB therapy achieve a good
4.4 | New drugs
hemodynamic response with carvedilol. In the same study, the use of
propranolol as a first-­line primary prevention followed by carvedilol in
4.4.1 | Statins may improve survival
those who did not hemodynamically respond to propranolol resulted
in a good hemodynamic response in 72%.23 Low doses of carvedilol Statins improve endothelial dysfunction in many vascular diseases due
(<25 mg/day) are as effective as relatively high doses (25-­50 mg/day) to its beneficial pleiotropic circulatory effects. Most effects are due to
in decreasing HVPG. Low doses (12.5 mg/day) of carvedilol are, there- enhanced expression of the KLF-­2 transcription factor and reported
fore, recommended, as high doses can cause arterial hypotension, genes (eNOS, thrombomodulin and angiopoietin). In experimental cir-
which may enhance sodium retention and worsen ascites. In a primary rhosis, statins (simvastatin and atorvastatin) decrease hepatic vascular
prophylaxis randomized controlled trial, carvedilol prevented a first resistance, improve endothelial dysfunction and decrease fibrosis. In
GEV bleeding episode more effectively than repeat EVL, although this patients with cirrhosis, statins moderately lower HVPG (even in pa-
requires confirmation in further studies.24 tients being treated by NSBB) and improve quantitative liver func-
tion tests but do not influence the systemic circulation.29 In a recent
RCT in patients who survived an episode of variceal bleeding adding
4.2 | Terlipressin is used for acute bleeding
simvastatin to the standard of care (NSBB and EVL) did not improve
Terlipressin—a long-­acting synthetic vasopressin analogue—is a po- the prevention of variceal rebleeding, but improved survival, mainly
tent splanchnic vasoconstrictor that also has systemic circulatory ef- by reducing the number of deaths due to bleeding and infections.30
fects, increasing arterial pressure and systemic vascular resistance, Large epidemiological surveys have shown that the progression of
and decreasing cardiac output. A single intravenous administration liver disease is reduced and mortality decreased in patients with cALD
leads to a marked decrease in the HVPG of more than 25%, which receiving statins.31
|
108      

T A B L E   2   Drugs for the treatment of portal hypertension

Propranolol Nadolol ISMN Carvedilol Terlipressin Somatostatin Octreotide Simvastatin

Beta-­1 and beta-­2 Beta-­1 and beta-­2 No donor Beta-­1 and beta-­2 Long-­acting Peptide hormone, Long-­acting Improves endothelial
adrenergic adrenergic adrenergic vasopressin inhibits glucagon SMT analogue dysfunction and reduces
receptor receptor receptor analogue and facilitates intra-­hepatic vascular
antagonist (NSBB) antagonist (NSBB) antagonist Splanchnic adrenergic resistance
(NSBB) with vasoconstriction, vasoconstriction
intrinsic anti-­α1 increase in
activity systemic vascular
resistance
Route Oral Oral Oral Oral Intravenous Intravenous Intravenous Oral
Dosage Start with 10-­20 mg Start with 20 mg Start with 10 mg Start with 2 mg injection every Bolus 250 μg Bolus 50 μg i.v., 20 mg once a day.
twice daily daily daily at night 3.125 mg twice 4 h for 24-­48 h, followed by followed by After 2 wk, increase to
Increase the dose Increase the dose Increase the daily then 1 mg/4 h for continuous i.v. continuous i.v. 40 mg/d if CPK and ALT do
every 2-­3 d up to every 2-­3 d up to dose after Increase the up to 5 d infusion 250-­ infusion 50 μg/h not increase over twice the
the maximal the maximal 2-­3 d up to dose every 2-­3 d 500 μg/h for up to for up to 5 d baseline values
tolerated dose tolerated dose 20 mg twice a up to 12.5 mg/d 5 d
Systolic blood Systolic blood day Systolic blood
pressure should pressure should pressure should
remain ≥ 100 mm remain ≥ 100 mm remain ≥
Hg and HR ≥ Hg and HR ≥ 100 mm Hg and
50 bpm 50 bpm heart
rate≥50 bpm
Max dose 320 mg/d 160 mg/d 40 mg/d 25 mg/d 8 mg/d for 24-­48 h 500 μg/h 50 μg/h 40 mg/d
4 mg/d thereafter
Side Bradycardia, Bradycardia, Headache, Arterial Abdominal pain, Hyperglycaemia, Hyperglycaemia, Elevated
effects orthostatic orthostatic orthostatic hypotension, arterial hyperten- vomiting vomiting aminotransferases (not more
hypotension, hypotension, hypotension Sodium sion; less than 3% frequent than in the general
Bronchospasm, bronchospasm, retention, ischaemia population)
erectile erectile ascites (peripheral, Up to 3% rhabdomyolysis in
dysfunction dysfunction intestinal or advanced cirrhosis (bilirubin
myocardial) >5 mg)
BRUNNER et al.
BRUNNER et al. |
      109

4.4.2 | Renin-­angiotensin-­aldosterone inhibitors: Cyanoacrylate


more studies needed injection

Although NSBB and ACE inhibitors and angiotensin receptor block-


EVL
ers lower the HVPG at a nearly similar rate and appear to be safe in
patients with good liver function (Child-­Pugh A),32 the role of these
agents in preventing GEV bleeding and the safety profile in decom-
pensated ACLD require further studies.

4.4.3 | Aetiologic treatments reduce portal pressure


with time
GOV 1 GOV 2
Studies in several liver diseases (hepatitis B, hemochromatosis, hepatitis
C, alcoholic liver disease) have shown that successful specific treatment
of liver disease can markedly reduce portal pressure. The time neces- Cyanoacrylate
sary for this beneficial effect varies and is probably longer in clinically injection
decompensated patients. This is highly relevant since the introduction
of direct acting antivirals for hepatitis C virus infection, which is one of
Cyanoacrylate
the main causes of cirrhosis worldwide. It is still uncertain whether the
injection
risk of portal hypertension-­related complications will completely disap-
pear, when this will occur and how it can be non-­invasively detected,
but these elements are being evaluated in large prospective studies.

4.4.4 | Antifibrotic drugs are promising IGV 1 IGV 2

Obeticholic acid (OCA) is a Farnesoid X receptor agonist, a nuclear re- F I G U R E   2   Gastroesophageal and isolated gastric varices:
ceptor in the liver and intestine that suppresses bile acid synthesis classification according to Sarin55 and choice of endoscopic
treatment [Colour figure can be viewed at wileyonlinelibrary.com]
and increases the transport of bile acids from hepatocytes into the
canaliculi. OCA significantly improves liver biochemistry in patients
with primary biliary cholangitis who do not respond to treatment with EVL is begun for acute bleeding or scheduled primary/secondary
ursodeoxycholic acid. OCA also improves the histological features of prophylaxis, it should be repeated every 2-­4 weeks until complete
patients with non-­alcoholic steatohepatitis (NASH). Further trials in “eradication” of the varices is obtained. The term “eradication” is
the field of primary biliary cholangitis, NASH, primary sclerosing chol- not literally the absence of varices, but defines varices that are ab-
33
angitis and biliary atresia are ongoing. sent or small (“remnants”) and cannot or need not be further ligated.
Simtuzumab, a monoclonal antibody directed against lysyl oxidase-­ This definition, therefore, involves a subjective component. After
like 2 (LOXL2) enzyme, was developed to target changes in fibrosis. In eradication, endoscopic screening at 1, 6, 12 months, and every
a mouse model, simtuzumab reduced bridging fibrosis, total collagen 12 months thereafter is recommended to detect recurrent high-­risk
expression and improved survival. In a recent open-­label safety trial, varices.
6 months of treatment with this agent was well tolerated in patients
with hepatitis C and/or HIV and advanced fibrosis, but did not affect
4.5.1 | Endoscopic therapy for gastric varices
liver histology.34 A large RCT in patients with NASH-­related cirrhosis
examining the long-­term effects of simtuzumab on liver histology and Isolated gastric varices (IGV1 and 2) and type 2 gastroesophageal
HVPG is in progress. varices (GOV2), which reach the stomach from the oesophagus on the
Emricasan, an anti-­apoptotic agent with anti-­inflammatory and antifi- side of the greater curvature (Figure 2), should be treated by endo-
brotic properties, has been shown to decrease portal pressure in a recent scopic variceal obliteration with intravariceal injection of a tissue ad-
35
pilot study in patients with cirrhosis as well as in experimental models. hesive (e.g. n-­butyl-­2-­cyanoacrylat). This has been shown to be more
effective than band ligation in acute bleeding from gastric varices. A
second glue injection into IGV 2-­4 weeks later can be considered to
4.5 | Endoscopic therapy: band ligation for
further reduce the risk of re-­bleeding. Although gastroesophageal
oesophageal varices and obliteration for gastric varices
varices type 1 (GOV1), which extend into the stomach on the side
Endoscopic variceal band ligation (EVL) is the endoscopic treatment of the lesser curvature, are usually treated with EVL, centres in Asia
of choice for oesophageal varices (EV) because it is more effective support using variceal obliteration with glue injection (Figure 2).10
and safer than endoscopic injection sclerotherapy (EIS). 36
Once Thrombin has been used instead of glue.37
|
110       BRUNNER et al.

4.6 | Interventional radiology treatments: 5.1 | Compensated patients without


intrahepatic shunts and retrograde gastroesophageal varices: prefer aetiologic treatments
obliteration of varices
In early stages, the goal of treatment is to avoid the progression of
Transjugular intrahepatic portosystemic shunt (TIPS) is a minimally in- cirrhosis to hepatic decompensation by preventing a further increase
vasive fluoroscopic-­guided procedure that creates a shunt between in portal hypertension. In this early stage, the aetiologic factors can
a hepatic vein and the intrahepatic portal vein sustained by a metal be targeted (e.g. antiviral treatment, alcohol withdrawal, weight loss,
stent. TIPS is a portosystemic shunt that is large enough to effectively phlebotomies and chelator therapy). Successful antiviral treatment
decrease portal pressure and small enough not to cause liver failure may lead to improvement of fibrosis, thus improving portal hyperten-
and hepatic encephalopathy. Ideally, it should maintain a portal pres- sion, although little is still known about how long this can take, if there
sure gradient (PPG, the difference between portal and inferior vena are “no-­return” points, and how this resolution can be assessed non-­
cava pressure) between 10 and 12 mm Hg. This requires progressive invasively. Exercise and weight loss have been reported to decrease
dilatation of the stent with balloon angioplasty catheters (usually up HVPG in obese patients independently of the underlying cause.41
to 8-­10 mm in diameter) while measuring the PPG. The use of stents Also, patients with ACLD should abstain from alcohol.10
covered with polytetrafluoroethylene (PTFE) is recommended to pre- The results of a large study in cACLD on the so-­called preprimary
vent occlusion of the shunt and maintain rates of primary unassisted prophylaxis of the development of GEV by long-­term administration
patency similar to those of surgical shunts.38 TIPS has almost com- of timolol (a NSBB) were negative.5,15 However, this study importantly
pletely replaced surgical shunts because of the reduced surgical mor- showed that risk of developing varices, and especially ascites, bleeding
bidity and mortality and similar efficacy. The main indications for TIPS or hepatic encephalopathy, is more frequent in compensated patients
are the treatment of acute variceal bleeding (as preventive therapy in with CSPH (HVPG of at least 10 mm Hg). Accordingly, the recommen-
high-­risk patients or as rescue therapy after failure of medical plus en- dations from the most recent Baveno conference state that the goal
doscopic treatment) and refractory ascites. TIPS is more effective than of therapy in these patients should be the prevention of decompen-
alternative therapy in both these indications and may decrease mor- sation. The preliminary results of a multicentre randomized controlled
tality. Evaluation of TIPS candidates should include a detailed history trial (ClinicalTrials number: NCT01059396) designed for this purpose
of previous episodes of HE, assessment of portal vein patency and suggest that the long-­term administration of propranolol (or carvedilol
anatomy on imaging, absence of biliary dilatation or tumours in the in patients whose HVPG does not decrease by at least 10% from base-
intrahepatic tract, and a transthoracic echocardiography. Because of line after intravenous propranolol) may prevent decompensation-­free
the risk of cardiac decompensation, TIPS is contraindicated in patients survival and almost halve the incidence of ascites.
with congestive heart failure, severe pulmonary hypertension and tri-
cuspid regurgitation. Recurrent episodes of HE, portal vein thrombo-
5.2 | Compensated Patients with Varices
sis and hepatocellular carcinoma are relative contraindications. HE is
more frequent in patients over 70 or with large bore shunts (12 mm
5.2.1 | Patients with small varices and no other risk
or more in diameter).38. HE occurs in about one third of the cases.
factors for bleeding: beta-­blockers
Although in most cases it can be managed medically, in about 6%-­
10% of patients HE is severe and may require closure or reduction The use of NSBB could be beneficial in patients with small (<5 mm)
of TIPS.39 EV without red colour signs and good/moderate liver function (Child-­
Balloon-­occluded retrograde transvenous obliteration (BRTO) is Pugh A/B), but this must be confirmed in further trials.
another minimally invasive procedure in which gastric or mesenteric
varices are retrogradely accessed from the femoral vein via a spon-
5.2.2 | Patients with “high-­risk” varices
taneous splenorenal shunt and occluded with tissue adhesives or
(primary prophylaxis of variceal bleeding): beta-­
thrombogenic intravascular coils. This method has been found to be
blockers or ligation
very efficient in controlling acute bleeding from gastric varices, but
no randomized controlled trials are available. It should be considered These include patients with small EV, but with red colour signs and/or
when endoscopic and medical therapies fail and the patient is not a Child-­Pugh C, and patients with medium or large (>5 mm) EV. The goal
good candidate for TIPS.40 of therapy is to prevent first variceal bleeding and other complications
from portal hypertension thus improving survival.
In patients with high risk but small varices, primary prophylactic
5 |  CLINICAL SCENARIOS FOR THERAPY treatment with carvedilol or a standard NSBB can be initiated.
In patients with medium or large varices (>5 mm), primary pro-
The treatment of varices and variceal haemorrhage vary based on phylaxis can be provided using either standard NSBB or carvedilol or
the clinical scenario and the previously described stages of ACLD. EVL. EVL is as effective and can be used as an alternative to NSBB
An overview of the different treatment strategies is provided in based on local resources and patient preferences. In general, EVL is
Table 3. the preferred option in patients with contraindications or intolerance
BRUNNER et al. |
      111

T A B L E   3   Overview of treatment goals and strategies for portal hypertension according to the clinical scenario

Baveno recommendations
regarding screening and Accepted pharmacological therapies and
Clinical scenario Goal of treatment surveillance endoscopy general measures

Compensated patients in whom Prevent No need for screening of Aetiologic therapy (e.g. alcohol withdrawal,
CSPH has been excluded by Progression to CSPH varices (no CSPH). antiviral therapy, weight reduction if over-
HVPG measurement weight/obese)
Compensated patients with Prevent development of Screen for varices Aetiologic therapy (e.g. alcohol withdrawal,
likely or confirmed CSPH varices If no varices are seen: antiviral therapy, weight reduction if over-
(LSM>20 kPa and/or platelet Prevent decompensation repeat endoscopy after 2 weight/obese)
count<150 G/L, or with or 3 y, depending on
measured HVPG≥10 mm Hg) presence or absence of
ongoing liver damage
if varices are present: see
below
Compensated patients with Prevent decompensation Repeat endoscopy after Aetiologic therapy (e.g. alcohol withdrawal,
small varices without RCS in Stabilize/lower portal 1 or 2 y, depending on antiviral therapy, weight reduction if over-
Child-­Pugh A/B pressure in order to reduce the presence or absence weight/obese)
the risk of variceal of ongoing liver damage NSBB can be considereda
progression
Compensated patients with Prevent the first variceal Begin NSBB or carvedilol Aetiologic therapy (e.g. alcohol withdrawal,
small varices with RCS AND bleeding episode No further endoscopies antiviral therapy, weight reduction if over-
decompensated patients Child Prevent decompensation if needed weight/obese)
C with small varices compensated NSBB/carvedilol
Prevent further decompensa-
tion if decompensated
Any patient with EV at least Prevent the first variceal Begin NSBB or carvedilol Aetiologic therapy (e.g. alcohol withdrawal,
medium/large in size or with bleeding episode EVL if intolerant or antiviral therapy, weight reduction if over-
gastric varices Prevent decompensation if contraindications to weight/obese)
compensated NSBB NSBB/carvedilol
Prevent further decompensa- No further diagnostic
tion if decompensated endoscopies needed
For patients on EVL:
repeat ligation every
2-­4 wk until complete
eradication of EV,
afterwards 1, 6, 12 mo
and every year
Acute variceal bleeding Achieve haemostasis N/A Vasoactive drugs and prophylactic antibiotics
Prevent rebleeding within 5 d Restrictive transfusion policy
Minimize 6-­wk mortality Perform endoscopy within 12 h (achieve
stabilization first)
EVL for EV and cyanoacrylate injection for
GOV2/IGV
Consider SEMS for refractory/massive bleeding
Consider early TIPS in high-­risk patients
(Child-­Pugh C<13 points or Child B with active
haemorrhage) and in patients with early
rebleeding within 5 d
Prevention of recurrent Prevent recurrent bleeding Repeated EVL every First option (standard): NSBBb +/− ISMN plus
bleeding after first Prevent other decompensa- 2-­4 wk until complete EVL
haemorrhage tion eradication, afterwards 1, If repeated EVL not possible: NSBB+/− ISMN
Improve survival 6, 12 mo and every year if NSBB not tolerated: consider TIPS
Consider adding simvastatin
After bleeding from gastric varices: consider
TIPS

CSPH, clinical significant portal hypertension; EV, oesophageal varices; EVL, endoscopic variceal band ligation; GOV, gastroesophageal varices; HVPG,
hepato-­venous pressure gradient; IGV, isolated gastric varices; ISMN, isosorbide-­5-­mononitrate; NSBB, non-­selective beta-­blockers; RCS, red colour signs;
SEMS, self-­expandable metal stent.
a
Insufficiently explored.
b
Role of carvedilol not yet defined.
|
112       BRUNNER et al.

to NSBB (after trying to switch to carvedilol, which is usually better endoscopy. All drugs are thought to be equally effective in control-
tolerated). However, contrary to NSBB, EVL does not prevent other ling bleeding and preventing re-­bleeding within 5 days, but the quality
complications of portal hypertension, such as bleeding from portal hy- of the evidence varies, because terlipressin is the only drug that has
pertensive gastropathy or colopathy, ascites and SBP.10,41,42 Gastric been shown to be effective to control bleeding, decrease transfusion
varices without previous bleeding can also be treated with NSBB.10 requirements and reduce the 6-­week mortality in placebo-­controlled
clinical trials.45 A recent large face-­to-­face study that showed equal
efficacy should be considered with caution because subtherapeu-
5.3 | Treatment of acute bleeding
tic doses of terlipressin and suboptimal doses of somatostatin were
Acute variceal haemorrhage is a medical emergency that requires used.46 Recommended doses are given in Table 2. Vasoactive drug
prompt and intensive medical care, ideally in an ICU. Initial manage- infusion is maintained for 2-­5 days.
ment should target control of the haemorrhage, prevent early (within
5 days) re-­bleeding, deterioration of liver function and other bleeding-­
5.3.2.2 | Endoscopic therapy
related complications, mainly infections, acute kidney injury and HE.
Emergency endoscopy should be scheduled as soon as possible, at
the latest 12 hours after admission; 250 mg erythromycin intrave-
5.3.1 |  GENERAL MANAGEMENT: nously prior to endoscopy accelerates the gastric emptying of clots
RESUSCITATION, ANTIBIOTICS AND and improves visibility during the endoscopy.10 A positive diagnosis
PREVENTION OF ENCEPHALOPATHY of variceal bleeding requires endoscopic confirmation of active bleed-
ing from varices, the presence of a fibrin clot (“white nipple” sign)
Resuscitation measures should follow the classical ABC (Airway, signalling the point of variceal rupture, or blood in the stomach with
Breathing, Circulation) principle to restore hemodynamic stability varices as the only potential source of the bleeding. EVL is indicated
and to maintain appropriate delivery of oxygen to the tissues. Airway in endoscopically demonstrated variceal bleeding and should be per-
protection with orotracheal intubation is mandatory in unconscious formed immediately (at the diagnostic endoscopy) by an experienced
patients or those with severe haemorrhage (hematemesis) before en- endoscopist. If the bleeding originates from GOV2 or IGV variceal
doscopy to prevent airway aspiration. Plasma volume expansion is pri- obliteration is preferred with injection of tissue adhesives.
marily infused for volume replacement. Packed red blood cells should Recommended treatment with combined vasoactive drugs and en-
be transfused restrictively (target haemoglobin level≈7 g/dL), because doscopic therapy (plus prophylactic antibiotics) results in successful 5-­
a less restrictive policy (target haemoglobin ≈9 g/dL) can increase mor- day control of bleeding in 85%-­90% of cases. After this period, NSBB
tality.43 This restriction does not apply to Child C patients, in cases treatment can be begun as secondary prophylaxis (see section 5.4).
of rapid ongoing bleeding or patients with a history of ischaemic car-
diovascular disease. Early prophylactic antibiotics, to prevent the occur-
5.3.2.3 | Preemptive TIPS
rence of infections after a bleeding episode and improve survival should
be also started on admission.44 The Baveno consensus conference rec- The above treatment strategy does not stratify therapy for the known
ommends the use of intravenous ceftriaxone 1 g/24 hours in patients risk factors. These are the presence of advanced liver failure (Child-­
with advanced cirrhosis, in areas with high prevalence of quinolone-­ Pugh C), active bleeding at endoscopy despite vasoactive drug infu-
resistant bacterial infections and in patients on previous quinolone sion and very high portal pressure (HVPG≥20 mm Hg). A multicentre
prophylaxis. The choice of the ideal antimicrobial prophylaxis must be RCT recently has shown that making an early decision to perform a
made in each centre depending on local antibiotic resistances. Also, the PTFE-­covered TIPS (during the first 24-­48 hours of admission), be-
patient’s individual risk factors (e.g. advanced cirrhosis and previous fore declaring treatment failure, resulted in decreased failure to con-
infections) must be taken into account.10 Furthermore, patients with trol bleeding, rebleeding and mortality in high-­risk patients.47 Patients
signs of infection on admission should be extensively evaluated and were either Child-­Pugh class C (<14 points) or Child-­Pugh class B and
treated. Prevention of HE: Lactulose per os, via a nasogastric tube or with active bleeding on endoscopy, with no contraindications to TIPS.
rectally, is recommended to prevent HE. Rifaximin may also be effec- Further studies have confirmed the findings of this important report,
tive, but has not been specifically investigated yet in these cases. but showed that survival is especially improved in class C patients.48
This approach is now recommended for approximately 20% of pa-
tients who fulfil these criteria and are treated in centres with enough
5.3.2 |  SPECIFIC THERAPY: FROM
experience with these procedures.
VASOACTIVE DRUGS TO TIPS

5.3.2.1 | Vasoactive drugs 5.3.2.4 | Treatment of patients that fail


standard therapy (“Rescue Therapy”)
When variceal haemorrhage is suspected, intravenous vasoactive
therapy (terlipressin, somatostatin or octreotide) should be begun. The most demanding situation is the treatment of patients in whom
This is usually started on arrival in the emergency room, before standard therapy with vasoactive drugs and endoscopic treatment
BRUNNER et al. |
      113

fails to control bleeding or the bleeding begins again within 5 days. such as ascites or portal vein thrombosis have already occurred. In
The recommended therapy in these cases is to perform an emergency secondary prophylaxis, the use of carvedilol is not recommended, be-
TIPS, if there is no contraindication. In case of non-­severe rebleed- cause data from RCT comparing carvedilol with NSBB in combination
ing within 5 days, treatment with vasoactive drugs is continued and a with EVL are lacking. Statins provided additional survival benefit in
second attempt with endoscopic therapy can be made before a rescue patients who survived an episode of variceal bleeding included in a
TIPS is considered. Rescue TIPS is very effective in controlling bleed- recent multicentre RCT, and should be considered in patients without
ing, but it is still associated with a high mortality of about 40%, prob- severe liver failure (benefit in Child C patients is unclear).30
ably because liver function markedly deteriorates during uncontrolled PTFE-­covered TIPS is better than standard secondary prophylaxis
bleeding until the TIPS is finally performed. BRTO may be considered (NSBB + EVL) in reducing the risk of rebleeding and is indicated in
in patients with refractory bleeding from gastric varices and a con- patients with recurrent bleeding on standard medical and endoscopic
traindication to TIPS. therapy. However, TIPS does not improve survival and is associated
with the development of HE in one third of patients.53,54

5.3.2.5 | Oesophageal Tamponade
5.4.1 | Secondary prophylaxis in special situations
Balloon tamponade with a Sengstaken-­Blakemore or a Linton-­Nachlas
tube may still be used in the very rare case of massive exsanguinating
5.4.1.1 | Fundal and ectopic varices
bleeding or recurrent bleeding as a “bridge” to TIPS or another defini-
tive treatment. However, oesophageal self-­expandable metallic stents Transjugular intrahepatic portosystemic shunt is indicated for the pre-
have been shown to be very effective49 and a recent RCT showed that vention of rebleeding from fundal varices (GOV2 and IGV1). In expert
oesophageal stents are as effective but safer than balloon tampon- centres, cyanoacrylate glue injection can be used as an alternative.
ade.50 This is part of current recommendations.10 In very selected cases (large gastro-­or splenorenal collaterals), BRTO
could be an option. Ectopic varices (IGV2), which are more frequent in
non-­cirrhotic portal hypertension, require a case-­by-­case assessment
5.4 |  PATIENTS WHO SURVIVE AN preceded by cross-­sectional imaging to map collateral vessels.
EPISODE OF VARICEAL BLEEDING: BETA-­
BLOCKERS, LIGATION AND TIPS
5.4.1.2 | Patients with complicated ascites
This clinical setting includes the so-­called secondary prophylaxis of Recent data have warned against the use of NSBB in decompensated
variceal haemorrhage, but as mentioned in the paragraph on primary patients with refractory ascites, HRS and/or SBP. Although data are
prophylaxis, the concept of improving outcomes in variceal bleeding is not conclusive, these studies do not support the decision to stop
evolving since the goal of therapy in these cases is to reduce the risk NSBB in all patients with complicated ascites. Nevertheless, the rec-
of death, and thus prevent the onset of complications of cirrhosis that ommendations of the Baveno VI consensus conference suggest that
can lead to death. They include re-­bleeding, but should not be limited blood pressure, sodium levels and kidney function should be carefully
to this, and all of them should be taken into account as endpoints in monitored and NSBB should be temporarily discontinued or reduced
future RCTs in this setting. in case of severe arterial hypotension, hyponatremia or acute kidney
The goal of secondary prophylaxis of variceal bleeding is to pre- injury.10
vent recurrent variceal haemorrhage once the first episode of bleeding
has been under control for at least 5 days, since the risk of rebleeding
is high (60% within first year) and associated with high mortality (up 6 | PERSONAL CONCLUSION
to 33%).41 The first-­line treatment includes standard NSBB lifelong
plus EVL until complete eradication of varices. As shown in a recent The treatment of portal hypertension has markedly improved in the
meta-­analysis, this combination is better than EVL alone to prevent past years, and we now have successful therapies that have increased
bleeding, but only slightly better than pharmacological therapy alone patient survival in each clinical scenario. This has been possible mainly
and has no effect on survival.51 Thus, NSBBs (combined with nitrates if by following a pathophysiological approach aimed at correcting the
tolerated) are the cornerstone of treatment. The most favourable out- basic disturbance, the increased portal pressure, by improving the
come is observed in patients with a good hemodynamic response to abnormalities causing it. There has been a continued systematic ef-
NSBB, namely those in whom the HVPG is decreased by at least 20% fort in converting each advance in knowledge into a new therapeutic
or below 12 mm Hg on treatment.52 The HVPG response should be target, in what should be considered an example of highly successful
measured regularly for better risk stratification and to guide therapy in translational research. This has been done in parallel with careful clini-
experienced centres. cal observations and cooperative efforts that have allowed better risk
Because EVL alone does not seem to provide sufficient protection stratification and the definition and standardization of treatment end-
from bleeding, TIPS should be considered in patients who do not tol- points, exemplified by the Baveno Consensus Conferences. We hope
erate NSBB rather than EVL alone, in particular if other complications that merging translational and clinical research efforts in the recently
|
114       BRUNNER et al.

launched Baveno Cooperation will continue to improve patient out- 19. Garcia-Pagan JC, Navasa M, Bosch J, et  al. Enhancement of portal
comes in the years to come. pressure reduction by the association of isosorbide-­5-­mononitrate
to propranolol administration in patients with cirrhosis. Hepatology.
1990;11:230–238.
CO NFLI CTS OF I NTE RE ST 20. Bureau C, Péron J-M, Alric JL, et al. ‘A La Carte’ treatment of portal
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None pertinent to this article. for the prevention of bleeding. Hepatology. 2002;36:1361–1366.
21. García-Pagán JC. Propranolol plus placebo versus propranolol plus
isosorbide-­5-­mononitrate in the prevention of a first variceal bleed:
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