Aasld Practice Guidance On Risk Stratification And.22

Received: 16 October 2023 | Accepted: 16 October 2023
DOI: 10.1097/HEP.0000000000000647
Practice Guidance
AASLD Practice Guidance on risk stratification and management of portal hypertension
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and varices in cirrhosis

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P U R P O S E AN D S C O P E Guidance (Box 1) therefore relate to ,2

OF THE GUIDANCE (1) recognition of the concept of David E. Kaplan1
compensated advanced chronic Cristina Ripoll3
This Practice Guidance from the liver disease (cACLD), a shift away Maja Thiele4
American Association for the Study from the requirement of a Brett E. Fortune5
of Liver Disease (AASLD) intends to histological or radiological diagnosis Douglas A. Simonetto6
coalesce best practice recommenda- of cirrhosis for initial patient risk Guadalupe Garcia-Tsao7
tions for the identification of portal stratification; (2) codification of Jaime Bosch8,9
hypertension (PH), for prevention of methodology to use noninvasive 1
Department of Medicine, Division of
initial hepatic decompensation, for assessments to identify clinically Gastroenterology and Hepatology, Perelman
the management of acute variceal significant PH (CSPH); and (3) School of Medicine, University of Pennsylvania,
hemorrhage (AVH), and for reduction endorsement of a change in Philadelphia, PA, USA
2
Gastroenterology Section, Corporal Michael J.
of the risk of recurrent variceal paradigm with the recommendation Crescenz VA Medical Center, Philadelphia, PA
hemorrhage in chronic liver disease. of early utilization of nonselective USA
3
The document updates and ex- beta-blocker (NSBB) therapy when Internal Medicine IV, Jena University Hospital,
Friedrich Schiller University, Jena, Germany
pands on the most recent preceding CSPH is identified in order to 4
Department of Gastroenterology and
Practice Guidance from the AASLD decrease the risk of cirrhosis Hepatology, Odense University Hospital,
related to the management of PH decompensation.[4] The updated Odense, Denmark; Institute of Clinical Research,
University of Southern Denmark, Odense,
and gastroesophageal varices that guidance further explores potential Denmark
was published in 2017,[1] itself an future pharmacotherapy options for 5
Department of Gastroenterology, Montefiore
update on the initial multisociety PH, clarifies the role of preemptive Medical Center, Albert Einstein College of
Medicine, Bronx, NY, USA
guidelines on this topic from 2007.[2] TIPS in AVH, discusses more recent 6
Division of Gastroenterology and Hepatology,
Since this latest AASLD Practice data related to the management of Mayo Clinic, Rochester, MN, USA
7
Guidance was published, the 7th cardiofundal varices, and addresses Yale University, New Haven, USA; VA-CT
Healthcare System, West Haven, CT, USA
Baveno consensus conference was new topics such as portal 8
Department of Visceral Surgery and Medicine,
convened in October 2021,[3] at hypertensive gastropathy (PHG) as Inselspital, Bern University Hospital, University
which international experts reviewed well as endoscopy prior to of Bern, Switzerland
9
Institut d’Investigacions Biomèdiques August Pi
data related to several key random- transesophageal echocardiography I Sunyer (IDIBAPS) and CIBERehd, University of
ized controlled trials (RCTs) and (TEE) and antineoplastic therapy. Barcelona, Spain
individual patient-data meta-analy- The present guidance does not
ses. Drawing from independent re- focus on ascites as a complication Correspondence
view of relevant studies as well as of PH because this was recently David E. Kaplan,
3400 Civic Center Drive, PCAM 708 South,
updated expert consensus, the most covered in the AASLD Practice Philadelphia, PA 19104.
significant changes in the current Guidance on ascites and related Email: dakaplan@pennmedicine.upenn.edu
Abbreviations: AASLD, American Association for the Study of Liver Disease; ACLD, advanced chronic liver disease; AVH, acute variceal hemorrhage; BRTO,
balloon-occluded retrograde transvenous obliteration; cACLD, compensated advanced chronic liver disease; CSPH, clinically significant portal hypertension; CTP,
Child-Turcotte-Pugh; ECI, endoscopic cyanoacrylate injection; EVL, endoscopic variceal ligation; FHVP, free hepatic vein pressure; GV, gastric varices; HE, hepatic
encephalopathy; LSM, liver stiffness measurement; MELD, Model for End-Stage Liver Disease; MRE, magnetic resonance elastography; NILDA, Noninvasive Liver
Disease Assessment; NSBB, nonselective beta-blocker; PH, portal hypertension; PHG, portal hypertensive gastropathy; pSWE, point shear wave elastography; RCT,
randomized controlled trial; SSM, spleen stiffness measurements; TE, transient elastography; TEE, transesophageal echocardiography; WHVP, wedged hepatic vein
pressure.
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AASLD PORTAL HYPERTENSION AND VARICES IN CIRRHOSIS
| 1181
complications[5] and vascular causes of PH.[6] The present stage (if using METAVIR or Kleiner staging system),
guidance is also meant to harmonize with the recently which is pathologically defined as the presence of
updated AASLD Practice Guidance on the use of TIPS, nodules of regenerating hepatocytes separated by
Variceal Embolization, and Retrograde Transvenous fibrous septa.
Obliteration in the Management of Variceal Hemorrhage.[7] Clinically, cirrhosis presents in two main clinical stages:
The present guidance specifically addresses PH in adults compensated and decompensated (Figure 1).[10] Per
with future guidance on the management of cirrhosis in recent consensus definition, decompensation is defined
children from the AASLD anticipated. by the development of clinically overt complications of
This AASLD Guidance provides a data-supported PH,[3] specifically overt ascites, variceal hemorrhage or
approach to the prevention and management of PH and overt hepatic encephalopathy (HE).[3] Although the
varices. It differs from the AASLD Guidelines, which are median survival in the patient who is compensated
supported by systematic reviews of the literature, formal exceeds 12 years, once a patient develops a
rating of the quality of the evidence, and strength of the decompensating event, median survival decreases to
recommendations. In contrast, this Guidance was less than 1.5 years.[11]
developed by consensus of an expert panel and provides Decompensation most commonly occurs when portal
guidance statements based on comprehensive review pressure gradients are at or exceed 10 mm Hg[12–15]
and analysis of the literature on the topic, with oversight (measured by the hepatic venous pressure gradient
provided by the AASLD Practice Guidelines Committee. described as follows). This pressure gradient defines
“clinically significant portal hypertension” or CSPH.[16]
Additional clinical features that are surrogate markers of
C O NT E XT O F P H IN C IR RH O S IS
CSPH include the presence of gastroesophageal
varices on endoscopy and/or portosystemic collaterals
Definition of PH
on cross-sectional abdominal imaging. Because of the
strong association with clinical outcomes, patients with
Portal vein pressure is proportional to splanchnic blood
compensated cirrhosis should be subclassified into
inflow and to the resistance opposing this flow. Portal vein
those without and with CSPH during clinical encounters
pressure is expressed as the portocaval pressure
preferentially using noninvasive tests discussed in
gradient, the pressure difference between the portal vein
Section 4.2.
(venous inflow into the liver) and the inferior vena cava
Among patients with decompensated cirrhosis, those
(that collects the venous outflow from the liver). Mea-
who develop successive complications (i.e., recurrent
surement of the gradient rather than absolute pressure
variceal hemorrhage, refractory ascites, hepatorenal
eliminates influence of changes in intra-abdominal
syndrome, spontaneous bacterial peritonitis, jaundice)
pressure.[8] In healthy participants, this pressure gradient
exhibit much higher mortality rates; this stage has now
ranges between 1 and 5 mm Hg; thus, PH in cirrhosis is
been designated as “further decompensation.”[17]
defined as a gradient greater than 5 mm Hg.
Because performing a liver biopsy to establish a
In all causes of PH, an increase in resistance to portal
diagnosis of cirrhosis and/or performing HVPG mea-
flow is the initial pathogenic mechanism, followed by an
surement to establish the presence of CSPH (which is
increase in portal venous inflow.[9] The site of increased
defined by an HVPG equal or greater than 10 mm Hg)
resistance forms the basis of the classification of PH into
are invasive tests that are not universally available, the
three main categories: (1) prehepatic, when the site of
usefulness of noninvasive tests to identify cirrhosis and/
increased resistance occurs in the portal vein prior to entry
or CSPH has been explored. A new entity designated
into the liver; (2) intrahepatic, when it occurs within the
“advanced chronic liver disease” (ACLD) denotes the
liver; or (3) posthepatic when it occurs after blood exits the
patient who, without a biopsy confirming it, is likely to be
liver through the hepatic veins (Table 1). Intrahepatic PH is
close to cirrhosis based on liver stiffness measurements
further subclassified into presinusoidal, with conditions
(LSM) and platelet count, and can be applied widely as
that affect the portal triad; sinusoidal, when the hepatic
a surrogate for advanced fibrosis/cirrhosis. The term for
sinusoids are affected (e.g., cirrhosis); and postsinusoidal,
patients with ACLD without prior decompensation is
with conditions that affect the efferent (central) vein. By far,
cACLD. LSM by transient elastography (TE) <10 kPa
the most common cause of PH is cirrhosis followed by
rules out cACLD and ≥ 15 kPA rules in cACLD.[18–21]
portal vein thrombosis.
(The AASLD NILDA of Portal Hypertension does not
advocate a specific cutpoint for LSM sufficient to rule in
Stages of cirrhosis CSPH). LSM by TE can be further used to rule in CSPH
at values > 25 kPa (in patients who are not
Histologically, the degree of fibrosis in chronic liver obese).[22–24] In those with intermediate LSM values,
disease can be evaluated semiquantitatively in liver platelet counts can be used to determine whether the
biopsy, with stages 0–2 defining early fibrosis stages, patient is likely to have CSPH, following the “Rule of
F3 bridging (advanced) fibrosis, and F4 the cirrhotic Five” (see Section 4.2 and Figure 3). LSM by TE should
1182
| HEPATOLOGY
not be used for clinical decision-making without

confirmation of high study quality and performance by TABLE 1 Classification of portal hypertension
adequately trained personnel. It is expected that other Classification Level Examples
elastography technologies will have validated cutoffs to Prehepatic Portal vein and Portal vein thrombosis
rule in and rule out cACLD and CSPH but, at the time of branches
writing, there are insufficient data to make specific Intrahepatic Presinusoidal Schistosomiasis, primary
recommendations. (portal triads) biliary cholangitis,
sarcoidosis,
portosinusoidal
vascular disorder
Resolution of PH Sinusoidal Cirrhosis (all causes),
alcohol-associated
Reductions in portal pressure induced by pharmaco- hepatitis

logical therapy or mechanically by placement of a TIPS Postsinusoidal Sinusodial obstruction
in patients with compensated or decompensated (central syndrome
cirrhosis decrease the risk of development of first or veins)
further decompensation and may improve survival.[9,15] Posthepatic Hepatic veins, Budd-Chiari syndrome,
Elimination of mechanical obstruction (e.g., inferior inferior vena congestive
cava hepatopathy (multiple
vena cava webs, portal vein thrombosis) and/or control
causes including but
of underlying liver disease through antivirals, immuno- not limited to
suppression, and alcohol cessation may also reduce pulmonary
portal pressure and lead to clinical recompensation and hypertension, heart
even to the resolution of cirrhosis in long-term follow-up failure, constrictive
pericarditis)
biopsies.[17,25] In the setting of elimination or control of
the underlying etiology, recompensation has been
clinically defined as the resolution of ascites and/or subsequently, elevated portal pressure (Figure 2).
HE no longer requiring specific therapy in the absence These structural changes are followed by splanchnic
of recurrent variceal hemorrhage for over 12 months vasodilation that augments portal blood flow,
together with stable improvement of liver function tests thereby further raising portal pressure. In addition to
(albumin, international normalized ratio, bilirubin).[3] “fixed” parenchymal architectural distortion, a dynamic
component caused by increased intrahepatic vascular
tone, mostly caused by reduced nitric oxide bioavailability,
P A T H O PH Y S I O L O G I C A L B A SE S O F accounts for about 30% of the total increase in
PHARMACOLOGICAL THERAPY intrahepatic resistance.[26] The pathogenesis of PH and
its complications is detailed in Figure 2. As detailed in
Overview Tables 2 and 3, these mechanisms represent the main
targets for pharmacologic and nonpharmacologic
In cirrhosis, the accumulation of fibrous tissue and nodule therapies for PH.
formation, with consequent vascular distortion, lead to an
increase in intrahepatic vascular resistance and,
Which is the optimal NSBB for PH?
BOX 1 What's new
The beneficial effects of NSBBs in PH are derived from
Recognition of the concept of compensated advanced chronic their ability to decrease portal pressure through a
liver disease (cACLD), a shift away from the requirement of a reduction in portal and collateral blood flow (Table 3).
histological or radiological diagnosis of cirrhosis for initial This is achieved by both decreased cardiac output (b-1
patient risk stratification blockade) and splanchnic arterial vasoconstriction (b-2
Codification of methodology to use noninvasive assessments blockade). Carvedilol, an NSBB that additionally exerts
to identify clinically significant portal hypertension (CSPH) intrinsic anti-alpha-1-adrenergic activity and facilitates
Endorsement of a change in paradigm with the the release of nitric oxide, induces intrahepatic
recommendation of early utilization of nonselective beta- vasodilation further reducing portal pressure.
blocker therapy when CSPH is identified in order to decrease
Carvedilol allows for a significantly more pronounced
the risk of cirrhosis decompensation
decrease in HVPG than traditional NSBBs (such as
Updated guidance on the use blood and blood products during
propranolol and nadolol[27]).
initial resuscitation of acute variceal hemorrhage
Carvedilol achieves a marked reduction in HVPG
Endorsement of preemptive TIPS in select patient subsets at low doses and does not require titration based on
Guidance on the use of upper endoscopy prior to resting heart rate. Because of liver metabolism,
transesophageal echocardiography
carvedilol is used in cirrhosis at lower doses than
| 1183
(A)
(B)
F I G U R E 1 The stages of cirrhosis and advanced chronic liver disease. (A) Clinical features, histologic findings, hepatic venous pressure
gradients (HVPG), and endoscopic features typical of compensated cirrhosis with and without clinically significant portal hypertension
(CSPH), decompensated cirrhosis, and further decompensated cirrhosis. Relative risk of death is indicated in the purple dashed line. (B) Liver
stiffness measurements and platelet counts used to characterize compensated advanced chronic liver disease (cACLD) and CSPH using
noninvasive, nonhistological criteria. HE, hepatic encephalopathy; VH, variceal hemorrhage.
used for heart failure. It is recommended that therapy activators/stimulators, anticoagulants, and anti-inflam-
is started at a dose of 6.25 mg per day and, if matory agents (Table 4), broadly target endothelial
tolerated, increased to 12.5 mg per day after dysfunction, microthromboses, and/or inflammation.
2–3 days (as a single dose or divided 6.25 mg bid), HMG-coA reductase inhibitors (statins) are of particular
with down-titration to 6.25 mg daily (single dose or interest following phase II studies that have shown
divided) if nontolerated or if systolic blood pressure significant effects on HVPG reduction and a single
falls below 90 mm Hg in compensated cirrhosis. double-anonymized RCT that demonstrated improved
Lower starting doses may be more appropriate in survival with the addition of simvastatin to standard
patients with Child-Turcotte-Pugh (CTP) class B and secondary prophylaxis after acute variceal
C cirrhosis.[28] About one third of patients with bleeding.[33–35] However, there are discrepant results on
compensated cirrhosis have arterial hypertension. In whether statins have additive effect with NSBB on HVPG
such cases, carvedilol doses may be further up- reduction.[33,36] Retrospective data suggest a decreased
titrated (up to 25 mg/day) for blood pressure control. rate of progression to cirrhosis, decompensation, and
Based on its greater reduction of portal pressure death in patients receiving statins and greater reduction
in head-to-head comparisons with traditional in HCC risk with lipophilic statins (simvastatin and
NSBBs,[29,30] a trend for better tolerance, simpler atorvastatin)[37] possibly related to differential
administration, possibility of preventing ascites, and a pharmacodynamics. Few prospective data exist to
potential survival advantage,[31,32] carvedilol is the guide statin selection in PH except for simvastatin,
preferred NSBB for management of PH. which should not be used at doses greater than 20 mg/
day in decompensated cirrhosis.[38] Atorvastatin
metabolism is altered in cirrhosis and there is less
Experimental pharmacological targets for experience with its use; as such, it may be prudent to use
prevention of progression low doses (10–20 mg) pending additional data.[39]
Presently, at least four prospective RCTs are testing
Novel therapeutic agents being explored to prevent or physiological or clinical endpoints with statins in CTP A or
treat PH, including but not limited to statins, cGT B cirrhosis.[38,40,41]
1184
| HEPATOLOGY
F I G U R E 2 Pathophysiology of portal hypertension and related complications. Portal hypertension results from a series of mal-
adaptive responses to chronic liver injury and cirrhosis. Initially, structural mechanisms because of accumulation of fibrous tissue,
regenerative nodules, microthrombi, parenchymal extinction, and collapse lead to an increase in intrahepatic vascular resistance (1). In
addition to architectural distortion, dynamic sinusoidal vasoconstriction contributes to 30% of the total increase in vascular tone. These
structural changes lead to an increased portal pressure gradient; when this reaches values of about 10 mm Hg, it gives rise to formation
of portal-systemic collaterals and compensatory splanchnic vasodilation, which, in turn, increases portal blood flow and, consequently,
portal pressure (2). One of the first consequences of portal hypertension is the development of portosystemic collaterals, for which
vascular endothelial growth factor (VEGF)-driven angiogenesis plays an important role (3). Gastroesophageal varices represent the
most clinically relevant collaterals because of their increased risk of bleeding. Bleeding is directly dependent on increased wall tension
at the varices, determined by portal pressure, variceal diameter, and thin wall thickness. Vasodilation occurs also in the systemic
circulation resulting in a hyperdynamic circulatory state, driven by decreased effective arterial blood volume leading to activation of
neurohumoral and vasoconstrictive systems, sodium and water retention, and increased cardiac output. This process eventually results
in the development of ascites and, at late stages, hepatorenal syndrome because of compensatory renal vasoconstriction. Hepatic
encephalopathy represents a multifactorial complication of portal hypertension, resulting from portosystemic shunting, impaired syn-
thetic liver function, increased bacterial translocation, and muscle wasting (sarcopenia). Finally, imbalances on vasoconstrictors and
vasodilators in the pulmonary circulation results in hepatopulmonary syndrome (increased vasodilation) and portopulmonary hyper-
tension (increased vasoconstriction). CO, carbon monoxide; H 2S, hydrogen sulfide; HVR, hepatic vascular resistance; NO, nitric oxide;
ET, endothelin.
| 1185
TABLE 2 Therapeutic targets in portal hypertension
Indefinitely or until TIPS

or liver transplant. No
indication for routine
Target Treatments
Maintenance
upper endoscopy
Cirrhosis
Etiological therapy Antiviral therapy (HCV, HBV),
immunosuppression (AIH), alcohol
abstinence and relapse prevention
therapy
Healthy lifestyle Alcohol elimination

Regular moderate aerobic exercise
Common adverse
Maintenance of body weight at body
mass index 18–29 kg/m2
hypotension,
bradycardia,
constipation
effects
orthostasis,
Adequate protein intake ( > 1 g/kg per
dyspnea,
day), avoidance of processed foods,
Fatigue,
avoidance of sugar and high-fructose
corn syrup–sweetened food
products, avoidance of salty foods,
tobacco avoidance
HR of 55–60 bpm if
High-protein nocturnal snack
No HR goal; SBP
tolerated; SBP
Increased hepatic TIPS Carvedilol
≥ 90 mm Hg
≥ 90 mm Hg
vascular resistance
Goal
maintained
maintained
should be
should be
Activated HSC Antifibrotic agents (experimental),
anticoagulants
LSEC dedifferentiation Statins
Hepatocyte injury Antioxidants
ascites: 160 mg/day

Splanchnic Nonselective beta-blockers and
ascites: 80 mg/day
12.5 mg/day (higher

vasodilation carvedilol
320 mg/day; with
160 mg/day; with

Maximal dose
doses could be
considered for
Without ascites:
Without ascites:
Terlipressin
indications)
nonhepatic
Somatostatin and analogs
Gut-liver axis Nonselective beta-blockers and
carvedilol
Fecal transplantation, probiotics,
antibiotics
Collaterals and Nonselective beta-blockers and
dose every
2–3 d until
twice daily
Increase the
Titration
varices carvedilol
treatment
Increase to
after 3 d
6.25 mg
Antiangiogenics (experimental)
goal
Endoscopic therapy
Collateral embolization, BRTO,
Nonselective beta-blockers used in portal hypertension
PARTO,esophageal stents, balloon

tamponade
20–40 mg
20–40 mg
bedtime
Starting
6.25 mg
dose
Abbreviations: SBP, spontaneous bacterial peritonitis; HR, heart rate.

twice
once
daily
daily
Abbreviations: AIH, autoimmune hepatitis; BRTO, balloon-occluded ret-

at
rograde transvenous obliteration; PARTO, plug occluded retrograde

transvenous obliteration.
vasoconstriction; caused by beta-
2 blockade leading to unopposed
Above plus decreased intrahepatic

Decreased cardiac output; caused
alfa-adrenergic vasoconstriction
vascular resistance; caused by

anti-alpha-adrenergic activity
by decreased heart rate and
Mechanism of action
Guidance statements:
adrenergic blockade, plus
contractility from beta-1
1. Carvedilol is recommended as the preferred

NSBB for the treatment of PH in patients with
Splanchnic arterial
cirrhosis.
2. The recommended maintenance dosage of
carvedilol is 6.25–12.5 mg/day. Maintenance
dosage can be given as a single daily dose or
divided twice daily. In patients with concomitant
arterial hypertension or cardiac disease, the
Propranolol
dose of carvedilol may be further increased to

TABLE 3
Carvedilol
Therapy
Nadolol
address nonhepatic indications.
1186
| HEPATOLOGY
D I A G N O S I S AN D M O N I T O R I N G
Recruiting (15)
Recruiting (14)
Recruiting (16)
recruiting
recruiting
Status
Recruiting
Recruiting
Recruiting
Hepatic vein wedge pressure
Unknown
Unknown
Not yet
Not yet
measurements
ACLF, acute-on-chronic liver failure; CSPH, clinically significant portal hypertension; CTP, Child-Turcotte-Pugh; NCT, National Clinical Trial; TBD, to be determined; VNT, varices needing treatment.
NCT04365868 (NAVIGATE)
Although direct portal pressure measurements can be
NCT03780673 (LiverHOPE)
NCT04072601 (STATLiver)
NCT03654053 (SACRED)
performed by means of endoscopic ultrasound or
NCT02508623 (ERASE)
percutaneous access, portal pressure is more com-

(CIRROXABAN)
monly determined indirectly by measuring the liver

NCT
NCT02643212
NCT04874428
NCT03720067
NCT04543643
NCT05161481
sinusoidal pressure by means of a transjugular catheter
placed into a hepatic vein. “Wedging” of the catheter to
occlude the hepatic vein lumen is achieved either by

advancing the catheter into a hepatic vein radicle or
more commonly by inflating a balloon at the tip of the
Switzerland
Country
catheter in a large hepatic vein, the latter being

Statesa
Denmark
States
Europe
United
United
considered the standard approach.[42,43] After occlusion,

China
Spain
Brazil
TBD
Italy
the pressure measured in the static column of blood

equals the pressure at the sinusoids. Because in
1,010
160
24
60
162
80
240
288
150
500
N
cirrhosis intersinusoidal communications are closed

because of the formation of nodules and fibrous septa,
the wedged hepatic vein pressure (WHVP) is equivalent
Hepatic decompensation or
Selection of ongoing clinical trials for novel pharmacological agents to prevent or treat portal hypertension
Death, LT, hospitalizations
to the portal vein pressure. The difference between

Hepatic decompensation
Progression of varices
WHVP and unwedged “free hepatic vein pressure”

Outcome(s)
Incidence of ACLF
Change in HVPG
Change in HVPG
Change in HVPG
Pharmacological
(FHVP; measured with the tip of the catheter introduced

about 2–3 cm into the hepatic vein) is the HVPG,
New varices
approximating the portacaval pressure gradient.

HCC
Accuracy of HVPG measurements can be increased

(1) by using balloon catheters to occlude the hepatic
vein (averaging the pressure in a larger territory); (2) by
Carvedilol-treated CSPH, incomplete response
Compensated cirrhosis with CSPH (clinical or
obtaining triplicate measurements; and (3) by following

Compensated cirrhosis with CSPH (clinical)
Compensated cirrhosis with CSPH (HVPG)
several simple measurement conventions (Box 2).[42,43]

HBV cirrhosis with VNT on carvedilol
Key inclusion criterion
HVPG provides valuable prognostic information in

A National Institutes of Health–sponsored multicenter trial also planned in the United States.
compensated and decompensated cirrhosis at

baseline,[42–45] in response to vasoactive drug therapy
Decompensated cirrhosis
(such as beta-blockers),[45–48] after elimination of the

cause of cirrhosis,[14,43,49,50] prior to resection operation
CTP A/B cirrhosis
NASH cirrhosis
for HCC,[51] and prior to any major operation in patients

with cirrhosis.[52]
HVPG)
HVPG measurement does not accurately estimate

portal pressure in presinusoidal PH, characteristic of
noncirrhotic primary biliary cholangitis, granulomatous
Duration
12 hours
diseases, and portosinusoidal vascular disorder (previ-

24 mo
18 mo
18 mo
24 mo
12 mo
12 mo
24 wk
2 mo
60 d
ously referred to as idiopathic PH or noncirrhotic

intrahepatic PH, with nodular regenerative hyperplasia
3
3
4
2
2/3
2/3
3
Ph
or periportal sclerosis as main histological

hallmarks).[43] In such cases, endoscopic screening for
complications of PH is recommended. Although HVPG
measurement may also be inaccurate in some patients
Simvastatin ±
Agent
Rosuvastatin
Rivaroxaban
Rivaroxaban
with NASH[53]; HVPG values, changes in HVPG, and

Atorvastatin
Simvastatin
rifaximin
Belapectin
BI 685509
Berberine
Rifaximin
CSPH do retain prognostic significance among patients

with NASH.[54,55]
Although measurement of HVPG has become the
inflammatory
gold standard to assess the presence and quantify the

Anticoagulant
TABLE 4
Microbiome
degree of PH,[42] it is moderately invasive and carries

Vasodilator
Unknown
small risks of injury related to access of the jugular vein,

Class
Statin
Anti-
induction of arrhythmias, and exposure to radiation.[56]

a
Interpretation of HVPG also requires specific expertise.
| 1187
BOX 2 ABCs of HVPG measurement
1. Consider the planned approach:

Approach Pros Cons Comments
Transjugular Fast, allows biopsy Potential for arrythmia Preferred at most centers
Transfemoral No risk of arrythmia Not adequate to obtain biopsy
Antecubital Less invasive Potential for arrythmia, unable to biopsy Rarely used
2. Select scale range to be 0–40 or 0–50 mm Hg. Adjust 1 grid mark = 1 mm Hg whenever possible and select low recording speed
(1–7.5 mm/s).
3. Use precalibrated transducers connected to a monitoring system with printing capacity or digital format that can be saved. Put transducer
level at midaxillary line.
4. Use balloon-tipped catheters of 10–12 mm balloon diameter.

5. Print calibration scale and zero level before any hemodynamic measurement.
6. Measurements should be obtained in a quiet ambience, asking the patient to breathe quietly and not to move or speak during
measurements. Patients should not be breathing deeply/snoring during measurements to avoid respiratory artifacts.
7. Do not use deep sedation (avoid fentanyl and propofol). Midazolam at low dose (0.02 mg/kg) is acceptable.
8. FHVP should be measured with the tip of the catheter 2–4 cm inside the hepatic vein. WHVP (after balloon inflation) should be obtained
at the same place, or more distally (if the vein is too large to be occluded by the balloon), after checking that there is no reflux of contrast
around the balloon or through another hepatic vein. Rinse the catheter thoroughly before measurements.
9. Run pressure measurements for 15–20 s for FHVP and for at least 1 min for WHVP because it may take a long time to stabilize. WHVP
should be read when stable, on the last 20–30 s.
10. Label each measurement. Discard measurements in which there are artifacts caused by moving, coughing, snoring, or speaking.
11. Run all measurements in triplicate. Sequential measurements should be within 2 mm Hg of the immediately prior measurement. Greater
variability should prompt reassessment of technique.
12. In addition to WHVP and FHVP, obtain measurements of the FHVP with the tip of the catheter 1–2 cm from the hepatic vein outlet into the
IVC. Obtain also the IVC pressure at the level of the hepatic vein outlet (close to the right atrium) and of the right atrial pressure. FHVP and
IVC pressure should be almost identical; if the FHVP exceeds > 2 mm Hg the IVC, obtain a venography to rule out any obstruction.
Abbreviations: FHVP, free hepatic vein pressure; IVC, inferior vena cava; WHVP, wedged hepatic vein pressure.
Together, these limitations restrict its routine use to Caution should be used in applying the “Rule of Five” in
specialized centers and as such have stimulated efforts patients with obesity and NAFLD/NASH, alanine
to validate noninvasive surrogates usable in regular aminotransferase increased > 3× upper limit of normal,
clinical practice. and primary sclerosing cholangitis with dominant stricture
(s) caused by poorer calibration.[23,59] For patients with
chronic viral hepatitis, alcohol-associated liver disease,
Noninvasive detection of CSPH and lean NAFLD (body mass index <30 kg/m2), an LSM
exceeding 25 kPa has a positive predictive value of > 90%
Conventional cross-sectional imaging such as ultra- for CSPH; however, the positive predictive value for this
sound, CT, and MRI have a limited but defined role for cutoff in patients with obesity and NASH is only 63%.[23]
identifying CSPH. Specific imaging surrogate markers There are insufficient data to support the utilization of
of CSPH include visualization of collaterals (perieso- any serological markers such as platelet count alone or
phageal varices, recanalization of the umbilical vein, enhanced liver fibrosis to exclude CSPH and eliminate
presence of splenorenal shunt) and presence of the need for endoscopy assessment to detect varices
ascites. Doppler-based sonographic assessments of needing treatment.
hepatic artery waveforms, pulsatility, or other surrogate Currently, the most robust estimation of CSPH is
markers of CSPH have moderate sensitivity and provided by the combination LSM (by TE) and platelet
specificity[57] and are not widely applied. count (Figure 3).[22,23,59] CSPH can be presumed in the
The best validated noninvasive staging system for presence of (1) LSM > 25 kPa, (2) LSM between 20 and
compensated cirrhosis is based on LSM by TE (FibroScan, 25 kPa and platelets < 150 K/mm3, or (3) LSM between
Echosens, France) and platelet count (Figure 1B).[3,58] The 15 and 20 kPA and a platelet count < 110 K/mm3. CSPH
“Rule of Five” has been proposed as a simple tool to can be excluded in patients with LSM < 15 kPa plus
quantify increasing relative risk of decompensation and platelets > 150 k/mm3. These cutoff values are highly
liver-related mortality and to define cACLD, CSPH, and the specific, but there remains room for refinement because
threshold for screening upper endoscopy (Figure 3). many patients remain unclassified (“gray zone”). Liver
1188
| HEPATOLOGY
F I G U R E 3 The use of noninvasive tests to stage and managed advanced chronic liver disease. Schema for using liver stiffness
measurement (LSM) by transient elastography to stage advanced chronic liver disease (ACLD), identify clinically significant portal hyper-
tension (CSPH), the stage-specific role of upper endoscopy to identify varices needing treatment (VNT), serial monitoring, and alternative
approaches. *ANTICIPATE model for HBV, HCV, alcohol-associated liver disease, and lean NAFLD (body mass index <30 kg/m2). Positive
predictive value (PPV) > 90% for LSM ≥ 25 kPa; PPV > 60% for the LSM + platelet criteria. **Baveno VI criteria for variceal screening.
*** ≥ 20% change accepted as clinically significant. ****Cutoffs for non-TE elastography methods and laboratory-based tests are not solidly
validated, and the cutoffs listed here should therefore be interpreted with caution. The green box to rule out compensated ACLD (cACLD) are
derived from normal range values and/or cutoffs for F0 vs. F1–4. 2D-SWE, two-dimensional shear wave elastography; ARFI; Acoustic
Radiation Force Impulse Imaging; BMI, body mass index; ELF, enhanced liver fibrosis; MRE, magnetic resonance elastography; Plt: platelet
count; TE: transient elastography.
stiffness-spleen size-to-platelet ratio has also proven to wave elastography, have been less well validated and
be an accurate surrogate marker of CSPH with values may be subject to cross-manufacturer variability. MRE
> 2.65 corresponding to a risk of CSPH above 80%.[59,60] and pSWE may be used to rule out cACLD across
When HVPG values exceed 10 mm Hg, spleen etiologies using platform-specific normal values (Figure 3).
stiffness measurements (SSM) by TE show a stronger Several studies, primarily in NAFLD, have evaluated MRE
correlation with HVPG than LSM.[61] SSM ≤ 46 kPa for fibrosis assessment on 1.5T MRI scanners with shear
may be particularly suited for ruling out varices needing wave frequencies around 60 Hz.[65–68] Although there may
treatment and eliminating need for endoscopy for be some minor differences between equipment at these
patients who would otherwise be selected for screening settings, MRE <3.5 kPa generally rules out cACLD, and
endoscopy using Baveno VI criteria (LSM ≥ 20 kPa, ≥ 5.0 kPa rules in cACLD.[67,68] Fourteen studies have
platelets <150 K/mm3).[58,62,63] Spleen length has been evaluated MRE for prediction of complications related to
suggested as a proxy for spleen stiffness because the PH, but only two compared MRE with the gold-standard
two exhibit a strong linear correlation.[64] However, the HVPG.[68–71] In the largest, most recent study, using
clinical utility of SSM and spleen length remains to be Siemens 1.5T equipment, a cutoff of 7.7 kPa diagnosed
validated because of (1) inclusion of only patients with CSPH with a moderate sensitivity of 78% and low
chronic viral hepatitis, limiting generalizability to ALD specificity of 64%. For pSWE, an LSM cutoff of greater
and NAFLD; (2) high technical failure rates (15%–27%) than 2.17 m/s may identify CSPH.[57] Cutoffs for LSM
for SSM; and (3) need for validation of a novel 100 Hz measured by non-TE elastography methods (MRE,
spleen-dedicated probe. pSWE, two-dimensional shear wave elastography) or
For LSM, non-TE elastography methods, such as laboratory-based tests to define CSPH are not currently
magnetic resonance elastography (MRE), point shear validated, as reviewed in the AASLD Noninvasive Liver
wave elastography (pSWE), and two-dimensional shear Disease Assessment (NILDA) Guideline.[72]
| 1189
Because of its well-established value in the clinical unless clinical recompensation has occurred and
evaluation of patients with ACLD, liver elastography discontinuation of NSBB or other decompensation-
measurements should be available in all centers related therapy is being considered.
caring for patients with ACLD. NILDA are best
calibrated for chronic viral hepatitis and ALD etiologies
but tend to overestimate CSPH risk in patients Monitoring changes in HVPG related to
with obesity and NAFLD.[23] Promising, but small therapy
and nonexternally validated, studies have reported

good correlation of contrast-enhanced ultrasound- There is no role of LSM or SSM for monitoring HVPG
derived,[73] MRI,[74] and serum biomarkers[75–78] with response to NSBB in the short- or long-term because
HVPG. However, as reviewed in the AASLD NILDA there is no correlation with HVPG in this setting.[89,90]
Guideline, correlations between blood-based NILDA SSM has been proposed as a better marker of changes
and CSPH remains inferior to those with imaging- in PH, but MRE-measured SSM did not correlate with
based NILDA.[72] In the absence of LSM or spleen acute NSBB response in one small study.[69]
stiffness, platelet count has only modest predictive
value for identifying CSPH[60] and no data-supported
recommendation can be made regarding the use of
platelet counts in isolation to guide endoscopic 3. Hepatic Venous Pressure Gradient (HVPG)
surveillance or NSBB initiation. measurement is the gold-standard method to
assess portal pressure in patients with cirrhosis.
Monitoring the development of CSPH, 4. Clinically significant portal hypertension (CSPH)
varices, and high-risk varices in the natural is defined as HVPG ≥ 10 mm Hg.
history of cirrhosis
5. HVPG may underestimate portal pressure in
Longitudinal studies investigating LSM by TE as a some patients with obesity and NASH-related
monitoring tool[79–84] suggest three clinical scenarios in cirrhosis.
which serial monitoring of patients with chronic liver 6. The presence of clinical decompensation, of
disease using NILDA are of relevance: (1) monitoring gastroesophageal varices on endoscopy, or
progression in patients with initial LSM 5–10 kPa in portosystemic collaterals or hepatofugal flow on
whom repeating LSM every 2–3 years may be imaging is sufficient to diagnose CSPH.
reasonable, individualizing intervals based on individual
risk of progression[21]; (2) confirming an initial LSM 7. CSPH can be noninvasively identified by LSM
suggestive of cACLD to reduce false positive by vibration-controlled TE (or non-TE
findings,[85–87] particularly in populations with low approaches when validated cutoffs exist) and
prevalence[88]; (3) monitoring progression in patients platelet count. CSPH is diagnosed at LSM
with initial LSM diagnostic of cACLD without CSPH, in ≥ 25 kPa irrespective of platelet count, LSM
whom repeating LSM by TE and platelet count annually 20–24.9 kPa with platelet count < 150 K/mm3, or
would be indicated to identify patients for whom NSBB LSM 15–19.9 kPa with platelet count <110 K/
should be initiated or screening endoscopy should be mm3.
performed.[3] 8. Annual LSM by TE (or non-TE approaches when
In published studies of cohorts of patients with viral validated cutoffs exist) and serum platelet
hepatitis or NASH, a ≥ 20% increase or decrease in counts may provide prognostic information in
LSM by TE appears to correlate with clinically relevant patients with cACLD without baseline CSPH in
deteriorations or improvement. In two studies in which a whom the underlying etiologies of cirrhosis
20% increase or decrease was used as a predefined remain active/uncontrolled.
endpoint, an increase of > 20% was associated with
increases in hepatic decompensation, whereas a
decrease of > 20% was associated with decreased
mortality.[82,83] A third study found an average 22%
increase in LSM in patients with HCV who decom- STAGE-SPECIFIC MANAGEMENT OF
pensated during follow-up, whereas patients free of PH
decompensation decreased LSM by 21%.[84] Conse-
quently, monitoring LSM in cACLD should only be Compensated cirrhosis without CSPH but
performed if a 20% change (increase or decrease) with mild PH (HVPG 6–9 mm Hg)
would alter patient management.
There is no role of measuring baseline or serial LSM As mentioned in Section 2.2, patients with cACLD can be
in decompensated cACLD (by definition with CSPH) subcategorized according to the presence or absence of
1190
| HEPATOLOGY
CSPH. The presence of CSPH is associated with an cirrhosis.[104,105] Similarly, use of low-dose aspirin might
increased risk of clinical decompensation[91] (see also reduce the incidence of HCC and
Section 5.2). liver-related mortality in patients with chronic hepatitis
All patients with compensated cirrhosis should B and C and seems to be safe in patients with
undergo regular imaging (every 6 months per AASLD compensated cirrhosis.[107]
guidance[92]) to screen for HCC and portal vein
thrombosis. In patients without CSPH, special attention
should be paid to imaging evidence indicating develop- Guidance statements:

ment of CSPH, such as detection of large collaterals
(i.e., recanalization of the umbilical vein or splenorenal 9. Use of NSBBs in patients with cirrhosis without
shunt) or presence of hepatofugal blood flow in the main CSPH is not recommended for prevention of
decompensation.
portal vein.[93]
Among patients without CSPH for whom NSBBs to 10. Lifestyle modification and treatment of
prevent decompensation are contraindicated or in underlying liver disease should be prioritized to
whom intolerance to beta-blockers is known, serial prevent progression to CSPH and
assessment for the need for EGD to identify high-risk decompensation.
varices remains important. Use of LSM measurement in
combination with platelet count (LSM < 20 kPA and
platelet count > 150 K/mm3, also known as Baveno VI
criteria) can identify patients in whom the likelihood of Compensated cirrhosis with proven or
high-risk varices is very low and therefore screening likely CSPH (HVPG ≥ 10 mm Hg)
EGD can be avoided.[94] A reevaluation of these
patients with platelet count and LSM is recommended Patients with compensated cirrhosis with CSPH as
on a yearly basis.[95,96] If LSM is not available, defined by an HVPG ≥ 10 mm Hg are at increased
endoscopic surveillance to identify CSPH should be risk of decompensation. Given low access and/or
performed unless there are surrogates of PH identified acceptance of HVPG measurements, other methods
by imaging, such as portosystemic collaterals. If to detect CSPH can be used in the clinic. The
identified, CSPH can be presumed and NSBB be presence of portosystemic collaterals, including vari-
initiated. There are insufficient data to recommend ces of any size, on endoscopy or imaging can be used
restricting endoscopy to candidates with platelet counts as a surrogate marker of CSPH.[93,108] Additionally, TE
<150 K/mm3 in the absence of TE (see Section 5.3). can identify patients with CSPH (see Section 4.2)
Treatment with beta-blockers in compensated cir- Data from one prospective trial and a systematic
rhosis without CSPH (previously termed “pre-primary meta-analysis[4,109] provide support for initiation of
prophylaxis”) is not indicated because beta-blockers NSBB to prevent decompensation in cACLD with
do not reduce the incidence of new varices, variceal CSPH. The PREDESCI study included 201 patients
bleeding, or clinical decompensation at this with compensated cirrhosis with CSPH without high-
stage.[91,97] risk varices who were randomly assigned to a beta-
Suppression or cure of the etiological cause of the blocker (propranolol or carvedilol, according to the
liver disease, lifestyle optimization (adequate nutrition, acute hemodynamic response to propranolol) or
normal body weight, avoidance of alcohol and other placebo.[4] NSBB were up-titrated to clinical tolerance
toxic substances) and control of comorbidities atten- as well as to maintain pulse ≥ 55 bpm and systolic
uate and/or reverse the progression of the liver blood pressure ≥ 90 mm Hg with planned upper limits
disease.[98–100] In NAFLD/NASH, obeticholic acid of 160 mg and 25 mg for propranolol and carvedilol,
(contraindicated with PH), lanifibranor, and semaglu- respectively. However, the mean dosages of propran-
tide have shown early promise in reducing fibrosis in olol and carvedilol actually achieved post-titration were
patients who are noncirrhotic.[101–103] It is presumed 95 mg/day and 19 mg/day, respectively. After 2 years
that improvement of fibrosis would prevent CSPH and of clinical follow-up, patients treated with NSBB
have a positive impact on the natural history manifested significantly lower risk of decompensation
of cACLD. (HR, 0.51; 95% CI, 0.26–0.97), predominantly a lower
Finally, some widely used medications for other risk of developing ascites, recently confirmed in a
indications may have beneficial effects in cirrhosis and Bayesian reanalysis.[110] Some caution should be
should not be discontinued because of recognition of made with applying these findings to all patients with
cACLD. The possible benefits of statins on cACLD have compensated cirrhosis and CSPH because of the
been discussed in Section 3.2. There are studies unique selection criteria of patients for this study; all
suggesting that metformin could be safe[104,105] and patients had confirmed CSPH by HVPG and were not
may reduce HVPG after a single dose,[106] the incidence selected for inclusion by NILDA. Additionally, the
of HCC, and decompensation in compensated majority of patients had untreated hepatitis C prior to
| 1191
availability of all-oral direct antiviral therapy, and the 15. Where TE is not available to diagnose CSPH,
effect of ongoing alcohol use was not assessed. In when empiric NSBB are contraindicated or not
subgroup analysis, patients with nonalcoholic liver considered due to prior intolerance,
disease and small varices appeared to have greater endoscopic surveillance of all patients with
benefit from carvedilol. cirrhosis is recommended. Patients with
In the absence of imaging surrogates of CSPH, in cACLD without varices on screening
which TE is not available, patients with cACLD should endoscopy should have endoscopy repeated
undergo surveillance endoscopy. Current guidance every 2 years (with ongoing liver injury or
related to surveillance intervals relies predominantly on associated conditions, such as obesity and
expert consensus based on studies of the natural history alcohol use) or every 3 years (if liver injury is
of variceal progression.[97,111–113] The prevalence of quiescent, e.g., after viral elimination, alcohol
varices among patients who were compensated at abstinence). Patients with cACLD without
baseline endoscopy was approximately 25%; among varices who develop decompensation should
those without varices, new varices were detected at a have a repeat endoscopy when this occurs.
rate of approximately 4.4–5% per year; conversion from The presence of varices of any size should
small to medium or large varices occurred within prompt initiation of NSBB (in absence of
1–2 years in 10–20% of individuals; annual incident contraindication).
bleeding occurred within 1 year in approximately 15% of
16. Where TE is not available, screening endoscopy
cases with large varices; and that the natural history is
is not necessary in patients on non-selective
significantly impacted by ongoing liver injury, in particular
beta-blocker therapy; the need for screening
continued alcohol use.[114] Based on this natural history,
endoscopy can be also obviated in some
consensus guidelines have evolved recommending that
patients on a selective beta-blocker by switching
patients with cACLD without varices who have ongoing
therapy to a non-selective beta-blocker after
liver injury should have endoscopy repeated every
discussion with the prescribing clinician.
2 years, and those without varices in whom liver injury
is quiescent, e.g., after suppressing hepatitis B virus
replication or obtaining a sustained virological response
(SVR) in patients with Hepatitis C virus infection, and
Compensated cirrhosis with a
alcohol abstinence, should undergo variceal surveillance
contraindication to or intolerance of beta-
every 3 years. Emerging data suggest that particularly
blockers
post-SVR, liver decompensation in patients who were
previously compensated may be so infrequent that
Patients with compensated cirrhosis who have contra-
surveillance may be discontinued after the first surveil-
indication for beta-blockers (see Box 3) or who do not
lance endoscopy shows no varices.[115]
tolerate beta-blockers have at present no further
therapeutic options to avoid clinical decompensation
Guidance statements: other than control of the underlying disease. Although a
11. In patients with compensated cirrhosis and possible benefit of statins to prevent decompensation in
CSPH, the goal of therapy is to prevent the this setting is pathophysiologically plausible[33] and
development of clinical decompensation. retrospective studies suggest that statins reduce the
incidence of decompensation,[116,117] to date, there are
12. NSBBs (preferably carvedilol 12.5 mg/day) insufficient data to recommend its routine use. Patients
should be considered for patients with cACLD with a standard indication for statin therapy should
with CSPH to prevent decompensation. continue treatment, and statins should not be
13. NSBBs should not be administered to patients discouraged when indicated.
with cACLD and evidence of CSPH with asthma, In patient with cACLD with CSPH for whom beta-
advanced heart block, and bradyarrhythmias, blockers cannot be safely administered, endoscopic
and caution should be used in patients with surveillance should be initiated with an intent to prevent
relative contraindications (Box 2). first variceal hemorrhage (primary prophylaxis) through
prophylactic endoscopic band ligation of high-risk vari-
14. Patients with cACLD and evidence of CSPH ces. Performance of an endoscopy every 2 years is
(by endoscopy, TE, HVPG or imaging) who are recommended; however, if cause of the liver disease is
candidates for NSBB should be considered for under control (alcohol abstinence, weight control, viral
treatment with NSBB (in the absence of suppression or elimination, etc.), endoscopic surveil-
contraindications) to prevent hepatic lance may be done every 3 years.[94] In some cases,
decompensation, which would also obviate the cessation of surveillance may be considered after
need for further screening endoscopy. negative serial endoscopic assessments in the setting
1192
| HEPATOLOGY
of complete disease resolution (e.g., sustained sobriety, 20. Band ligation should be repeated every 2–4
SVR after HCV direct-acting antiviral therapy with weeks until obliteration and then endoscopy
complete normalization of aspartate aminotransferase repeated at 6 months and then every
and alanine aminotransferase), LSM < 12 kPa, and 12 months to assess for reappearance of
platelet > 150 K/mm3.[118] varices requiring additional treatment.
If endoscopic variceal ligation (EVL) is selected for
21. TIPS should not be used for the prevention of
primary prophylaxis of high-risk varices, EVL should be
decompensation of cirrhosis or as primary
repeated until all varices are eradicated. Intervals

prophylaxis for variceal hemorrhage.
between endoscopies evaluated in clinical trials for
primary and secondary prophylaxis have ranged from 1
to 8 weeks.[119–124] In a prospective randomized trial for
secondary prophylaxis, no difference in overall oblitera-

tion rates after 3 endoscopy sessions was demonstrated
Primary prophylaxis to prevent variceal
in patients undergoing repeat endoscopy every 2 weeks
hemorrhage in dACLD
(at week 2 and week 4) compared with those selected to
undergo endoscopy every 8 weeks (at week 8 and week Patients who have decompensated cirrhosis by definition
have CSPH. Increasing CTP class, variceal size, and
16), with persistent banding ulcers only observed in the
presence of variceal red wale marks are associated with
every 2 week arm, and higher rates for reintervention
an increase in the risk of a first variceal hemorrhage.[128]
during long-term follow-up required in the every 2 week
Patients with high-risk varices (moderate/large varices or
arm.[125] In a more recent study, repeat endoscopy after
any size varices with red wale marks or in a patient with
AVH every 1 week showed no superiority to repeat
CTP C) should undergo primary prophylaxis to prevent
endoscopy every 2 weeks until eradication with regard to
variceal bleeding. If the high-risk varices are small, the
recurrent bleeding, safety, or mortality.[126] Based on
limited data, a recommendation was made for an interval only method that is technically feasible is the adminis-
tration of NSBB. If the high-risk varices are large, both
of 2–4 weeks, favoring 4 weeks to allow banding ulcers to
NSBB as well as EVL are possible approaches; however,
heal. After eradication, periodic endoscopy should be
a recent systematic review with network meta-analysis
repeated every 6–12 months.
showed that EVL is associated with a higher risk of
Studies from the 1960s and 1970s showed that the
complications and higher mortality than NSBB.[129] The
use of surgical shunts to prevent first variceal bleeding
administration of carvedilol in patients with high-risk
increased the incidence of HE and increased
varices and ascites has been associated to an improved
mortality.[127] It has been extrapolated from these data
that prophylactic TIPS to prevent first variceal hemor- survival in a prospective study (HR, 0.41; 95% CI,
0.19–0.96)[130] and a retrospective study (HR, 0.61; 95%
rhage in the setting of compensated cirrhosis with high-
CI, 0.46–0.81).[131] A retrospective long-term follow-up of
risk varices should not be recommended.
patients included in a previous RCT comparing carvedilol
to EVL for primary prophylaxis, in which half of the
17. Patients with compensated cirrhosis and CSPH
BOX 3 Contraindications to nonselective beta-blockers
without varices who have contraindications or
intolerance to beta-blockers should be screened Absolute contraindications
for varices needing treatment with surveillance Asthma
endoscopy every 2 years when the underlying
2nd and 3rd degree atrioventricular block (in absence of
disease remains uncontrolled and every 3 years implanted pacemaker)
when controlled. Sick sinus syndrome
18. Patients with compensated cirrhosis and CSPH Extreme bradycardia (< 50 bpm)
with varices that have not bled who have Relative contraindications
contraindications or intolerance to beta-blockers
Psoriasis
should be screened for varices needing
Peripheral arterial disease
treatment with surveillance endoscopy every
1 year when the underlying disease remains Chronic obstructive pulmonary disease
uncontrolled and every 2 years when controlled. Pulmonary artery hypertension (controversial)
19. Primary prophylaxis with EVL should be Insulin-dependent diabetes mellitus (interferes with
symptoms of hypoglycemia)
performed in patients with cACLD and CSPH
and high-risk varices that cannot Raynaud syndrome
receive NSBBs.
| 1193
patients had ascites and approximately two thirds of the advancements for AVH, 6-week mortality still ranges
patients were CTP class B and C at baseline, found a from 10% to 15%.[1,94] Hemorrhage results from variceal
survival benefit related to randomization to carvedilol wall rupture because of increased wall tension, itself
compared with EVL (median survival of 7.8 vs. 4.2 y).[132] related to elevated variceal transluminal pressure,
This effect could be mediated by a decrease in the increased variceal diameter, and decreased wall
incidence of further decompensation among patients thickness.[146] The incidence of AVH correlates with the
who receive NSBB.[15,133–135] magnitude of PH (HVPG measurement, NILDA), severity
The safety of NSBB among patients who have of liver disease (e.g., CTP class or Model for End-Stage
ascites and refractory ascites has been an issue of Liver Disease [MELD] score), and varix characteristics
extensive discussion in the past decade since an initial (size, red wale signs).[17,45,147–149] Most deaths from AVH
publication suggesting an increased mortality among occur in patients with CTP C; patients with CTP A rarely
patients with refractory ascites and beta-blockers.[136] die from variceal bleeding. Tailoring treatment
However, in this study most patients were given approaches to patient characteristics therefore remains
unusually high doses of propranolol (160 mg of long- critical.
acting propranolol per day). In the interim, several The mainstay of AVH management includes maintain-
studies have shown that NSBB in patients with ascites ing adequate systemic organ perfusion and oxygenation
and even refractory ascites are safe and potentially while achieving hemostasis but avoidance of worsening
beneficial.[137–141] However, low systolic blood pressure portal pressure (Figure 4). On presentation of
(< 90 mm Hg) may attenuate the survival advantage gastrointestinal hemorrhage, those with known or
associated with NSBB use[142,143] possibly by reducing suspected history of advanced liver disease should be
renal perfusion pressure increasing the risk of hepa- managed as having a portal hypertensive-related source
torenal syndrome–acute kidney injury.[144] In patients until endoscopic confirmation. Patients presenting with
who have low arterial blood pressure with low doses of AVH should be transferred to a medical care unit that
carvedilol, one may consider a switch to a traditional provides proper levels of nursing and medical care, such
NSBB such as propranolol or nadolol because these as an intensive care unit. Placement of adequate
agents usually have lesser effects on arterial intravenous access and airway assessment are initial
pressure.[143,145] measures for resuscitation. For those with altered
mentation or risk of aspiration, an endotracheal tube
should be placed prior to upper endoscopy. Given
increased mortality risk while intubated, providers should
22. Patients with decompensated cirrhosis not attempt extubation as soon as deemed safely possible.[150]
taking NSBBs who have never bled from Vasoactive therapy (Table 5) that is aimed to reduce portal
varices should undergo annual endoscopic pressure and collateral blood flow[159,160] as well as
screening. antimicrobial prophylaxis should be initiated immediately
23. If high-risk varices are detected, NSBBs or on presentation and maintained for 2–5 days.[1,159,160]
endoscopic band ligation are recommended; Intravenous antimicrobials are recommended until stability
preference is given to NSBBs (including for discharge or 5 days, whichever is shorter, in the
carvedilol) because of benefits beyond absence of active infection. Intravenous ceftriaxone dosed
prevention of variceal hemorrhage. (If at 1 g every 24 hours is often preferred because of high
endoscopic band ligation is chosen, refer to rates of quinolone resistance; however, systemic anti-
recommendation 19). microbial choice should be tailored to local hospital
antimicrobial resistance and stewardship policies.[161–164]
24. NSBBs should be dose reduced or Because aspiration pneumonia is the most common
discontinued in patients who develop infection to develop in patients admitted for variceal
persistently low systolic arterial pressure bleeding,[165] care should be taken at endoscopy and any
<90 mm Hg or severe adverse effects. NSBB intervention that involves the airway; routine pre-endo-
discontinuation should prompt endoscopic scopic or preintubation placement of nasogastric tubes
evaluation for presence of high-risk varices should be discouraged. Packed red blood cell transfusion
requiring band ligation. goals should be restricted for a target hemoglobin of about
7 g/dL in the absence of comorbidities (e.g., ischemic
coronary disease) or instability that might merit higher
targets.[166,167] Furthermore, coagulation parameters such
AVH, initial bleed as international normalized ratio do not predict hemostatic
dysfunction, and liberal transfusion of frozen plasma and
AVH remains an emergent complication of cirrhosis other blood products should be avoided to prevent worse
and requires timely and effective management to survival and worsening portal pressure.[166,168,169] Once the
prevent short-term mortality. Even with therapeutic patient is stable, abdominal imaging with either contrast-
1194
| HEPATOLOGY
enhanced cross-sectional modality (CT or MRI) or still associated with lower mortality than standard
ultrasonography with Doppler should be performed to therapy.[187] Transplant candidacy should be promptly
evaluate for portal venous thrombosis as well as presence assessed in such patients. For those who have early
of liver cancer. In addition, cross-sectional imaging would hemostasis but develop rebleeding within the first 5 days
assist in patients needing endovascular procedures. post-bleed, providers may proceed with repeat endos-
Timely upper endoscopic evaluation should be copy and treatment based on findings; however, this is a
performed (within 12 hours of AVH presentation) to high-risk situation for which “rescue” TIPS may be the
determine source of bleeding and therapy.[170,171] If optimal approach in the absence of contraindications.[178]
varices are visualized, the endoscopist can determine Once hemostasis, hemodynamic stability, and nor-
location of varices, if actively bleeding, and presence mal mentation have been restored, oral nutrition must
of varix characteristics (large column size, red wale be started immediately to avoid malnutrition.[188] Proton
signs). EVL, repeated after discharge every 2–4 pump inhibitors should be discontinued in the absence
weeks until variceal obliteration, should be the of absolute indications because of increased risk of
standard endoscopy approach for esophageal infection and encephalopathy.[189–191] NSBBs can
varices.[172] Intravenous erythromycin 125–250 mg be introduced once patients can tolerate oral intake.
given 30–120 minutes before endoscopy has been Vasoactive therapy should be subsequently discontin-
shown to facilitate visualization and therapy.[173,174] ued concomitant with NSBB initiation and not later
Management of bleeding gastric and ectopic varices than day 5.
will be discussed as follows. If immediate hemostasis
is not achieved, patients with ongoing bleeding should
have endotracheal tube placement and proceed with Guidance statements:
balloon tamponade or esophageal stenting as a 25. All patients with known or suspected cirrhosis
temporizing measure. Depending on local availability presenting with acute gastrointestinal bleeding
and expertise, use of specialized esophageal self- should be initiated on vasoactive therapy (e.g.,
expandable metal stents (not FDA approved in the somatostatin, octreotide or terlipressin if
United States) can also be used to achieve hemosta- available; see Table 5) and intravenous
sis with similar efficacy and improved safety compared antibacterial therapy as soon as possible.
with balloon tamponade.[175–177] Esophageal stents
26. If portal hypertensive bleeding is confirmed at
have the advantage that they can be kept in place for
endoscopy, vasoactive therapy should be
up to 1 week, compared with balloon tamponade,
continued for 2–5 days.
which is limited to 24 hours. Emergent placement of
TIPS using a polytetrafluoroethylene-covered stent 27. Intravenous antibacterial treatment should be
may be considered before removing balloon tailored to local resistance patterns and
tamponade or esophageal stent.[178] Many centers patient allergies. The most commonly used
administer prophylactic lactulose or rifaximin to agent is ceftriaxone 1 g/24 hours up to 5 days.
decrease the risk of HE after TIPS based on data from Antimicrobial therapy can be discontinued
RCTs.[179,180] once bleeding is controlled and in absence of
For specific patients who are high risk and have AVH, an active infection.
“early” or preemptive TIPS improves both bleeding
28. Packed red blood cell transfusions should
control as well as survival in most[50,181–183] but not all
target a hemoglobin ~7 g/dL unless higher
studies.[184] Specifically, patients with CTP class B score
targets required related to comorbid
> 7 with active bleeding on endoscopy and CTP class C
conditions.
score 10–13 should undergo TIPS within 24–72 hours of
initial endoscopy. Similar recommendations are made for 29. Fresh frozen plasma and platelet transfusions
those who have had HVPG measurements > 20 mm Hg should not be administered based on
obtained,[185] although measuring pressure in this setting international normalized ratio or platelet count
is challenging and is not recommended. It is important to targets, respectively, because there is no
emphasize that studies that evaluated early TIPS evidence of benefit of such transfusions in
excluded older and pregnant patients, patients with AVH, and in the case of fresh frozen plasma,
nonearly stage HCC, severe acute or chronic kidney there is evidence of potential harm.
disease, patients on secondary prophylaxis for prior
30. Upper endoscopy should be performed within
hemorrhage, nonesophageal variceal bleeding, com-
12 hours of presentation with AVH.
plete portal vein thrombosis, and heart failure. In
retrospective studies, high rates of mortality despite 31. If esophageal variceal bleeding is confirmed,
intervention have been observed in this setting for EVL should be performed.
patients with MELD score > 19,[186,187] but early TIPS is
| 1195
32. In patients with CTP class B score > 7 and 36. Enteral feeding should be started once AVH
active bleeding on endoscopy or CTP class C episode has been controlled. The presence of
score 10–13, preemptive TIPS creation variceal bands does not contraindicate
(within 72 hours and ideally within 24 hours of placement of a feeding tube if indicated.
initial upper endoscopy) should be recom-
37. Proton pump inhibitors should be discontinued
mended in absence of absolute contraindica-
once AVH has been confirmed as the bleeding
tions to TIPS. If TIPS is not locally available,
source in the absence of other specific
transfer to a center with the capacity to

indications.
intervene should be considered.
33. In patients presenting with AVH who do not
undergo TIPS, NSBB should be initiated at
discontinuation of vasoactive therapy.

Prevention of recurrent hemorrhage after
34. Covered expandable esophageal stents initial bleeding
(where available) or balloon tamponade
should be considered in patients with After an episode of first AVH, patients are at high risk of
uncontrolled AVH as a bridge to TIPS. rebleeding (up to 60% at 1 y without prophylaxis).[127]
35. TIPS should be considered in patients with Secondary prophylaxis to prevent rebleeding should be
uncontrolled AVH (“salvage” TIPS) or who instituted immediately after control of the index bleed,
rebleed despite vasoactive therapy and EVL within 7 days from admission, because the highest risk
(“rescue” TIPS). period for rebleeding is the first 6 weeks after
presentation.[192] In patients who underwent preemptive
TIPS, no further measures are required. Those without
preemptive TIPS should receive secondary prophylaxis
(A) (B)
F I G U R E 4 Management of acute variceal bleeding. Initial management of a patient with upper gastrointestinal bleeding that could be
variceal in origin includes routine cardiopulmonary resuscitation, a conservative strategy for red cell transfusion, avoidance of routine fresh
frozen plasma (FFP) and cryoprecipitate, prompt initiation of vasoactive therapy and antimicrobial prophylaxis. Upper endoscopy is recom-
mended within 12 hours with specific pathways provided for (A) esophageal and/or GOV1 bleeding, (B) GOV2/IGV2 or ectopic varices, and
nonvariceal causes. BATO, balloon-occluded antegrade transvenous obliteration; BRTO, balloon-occluded retrograde transvenous obliteration;
CARTO, coil-assisted retrograde transvenous obliteration; CTP, Child-Turcotte-Pugh; NSBB, nonselective beta-blocker; pSAE: procedure
related Serious Adverse Event; US, ultrasound.
1196
| HEPATOLOGY
approach for secondary prophylaxis should be reserved

TABLE 5 Vasoactive agents for acute variceal bleeding. for patients with other indications for TIPS, such as
Agent Dosing Duration recurrent/refractory ascites, where it may improve
Octreotide Initial i.v. bolus of 50 mcg and 2–5 d survival.[203] The use of TIPS as first option in secondary
continue infusion at a rate of prophylaxis in other high-risk groups has not been
25–50 mcg/hour[151–153] adequately studied so far. TIPS is recommended for
Somatostatin Initial i.v. bolus of 250 mcg and 2–5 d patients who rebleed despite adequate secondary
continue infusion at a rate of prophylaxis, especially those with rebleeding within

250–500 mcg/hour[154,155]
the first 6 weeks.[204]
Terlipressina Initial 24–48 hours: 2 mg i.v. 2–5 d
every 4–6 hours and then 1 mg
i.v. every 4–6 hours Guidance statements:
[154,156–158]
38. Patients with variceal bleeding who do not fulfill
a
Not approved for this indication in North America.
[ ] the criteria for a preemptive TIPS and/or do not
References: Garcia-Tsao et al. Hepatology. January 2017 1 ; Seo et al.
Hepatology. September 2014.
[159] undergo TIPS during admission should
undergo secondary prophylaxis with NSBB and
endoscopic band ligation.
with NSBBs and endoscopic band ligation.[193–195] When 39. Use of TIPS for secondary prophylaxis can be
compared with EVL alone, the combination of EVL and considered in patients with additional
NSBB reduced rebleeding in all categories of patients and indications for TIPS (e.g., refractory ascites).
improved survival in patients with CTP class B and C.[196]
Propranolol, nadolol, and carvedilol may be used for
secondary prophylaxis[29]; carvedilol has greater effects
on HVPG reduction but a higher potential to cause GASTRIC AND ECTOPIC VARICES
systemic hypotension.[197] The use of isosorbide mono-
nitrate to enhance the portal pressure response to NSBBs Gastric varices (GV) are commonly classified according
has been almost abandoned since the advent of to the Sarin classification.[205] This classification divides
carvedilol. A multicenter double-anonymized RCT dis- GV among those that are a continuation of esophageal
closed a reduced mortality when simvastatin was asso- varices along the lesser curvature (GOV1) or greater
ciated to propranolol and EVL in patients surviving an curvature (GOV2) and isolated GV, which can be found
episode of AVH, which was related to preventing deaths in the fundus (IGV1) or in other areas of the stomach
after acute-on-chronic liver failure precipitated by infec- (IGV2). Varices along the lesser curvature (GOV1) share
tions or bleeding.[33] These findings, although supported a natural history and can be treated comparably with
by experimental data,[198] await clinical confirmation. esophageal varices. Varices along the greater curvature
When AVH occurs despite primary prophylaxis, (GOV2) and in the fundus (IGV1) are frequently referred
patient adherence with EVL and NSBB, and NSBB to as cardiofundal or gastric fundal varices and have a
dosage, should be evaluated. True failure of primary different natural history than esophageal varices.
prophylaxis with NSBB (propranolol or nadolol) is Although acute hemorrhage from esophageal varices
associated with a persistently high risk of rebleeding occurs far more commonly, bleeding cardiofundal varices
and death despite addition of EVL[199] for secondary are associated with higher rates of treatment failure,
prophylaxis. In such patients, one may consider adding rebleeding, and mortality.[205–207]
isosorbide mononitrate,[200] switching the NSBB to The prevalence of GV ranges between 17% and 25%
carvedilol given its greater portal pressure-reducing among patients with cirrhosis that have not bled. GV are
effect,[197] or consider adding simvastatin to NSBB and more common among patients with prehepatic PH,
EVL, a strategy that in a single RCT was associated particularly in those with splenic vein thrombosis causing
with reduced mortality despite no effect on variceal left-sided or sinistral PH, than among those with
rebleeding.[33,34] Simvastatin should be used with sinusoidal PH.[1,43,205–211] Therefore, when GV are iden-
caution in patients with total bilirubin > 3 mg/dL and tified, contrast-enhanced cross-sectional imaging should
used only at low doses (10–20 mg/day) in patients with be performed to rule out vascular thrombosis.[211] The
CTP B–C because of the risk of rhabdomyolysis.[38] presence of GV or ectopic varices indicate the presence
TIPS when used as first-line therapy for secondary of CSPH,[93] but GV typically evolve and bleed at lower
prophylaxis is associated with lower rebleeding rates portal pressure than do esophageal varices.[210] The
compared with EVL + NSBB but has no impact on incidence of bleeding from cardiofundal varices is
survival and is associated with higher rates of reported around 16% and 45% at 3 years.[206,207]
HE.[201,202] Therefore, TIPS placement as first-line Predictors of bleeding among patients with GV appear
| 1197
similar to those of esophageal varices: size ( > 10 mm for

cardiofundal varices), presence of red marks, and liver
disease severity.[1,128,212–214]
Rectal, stomal, and other ectopic varices may be 40. Patients with gastric or ectopic varices have
identified among patients with cirrhosis and CSPH and therefore the use of NSBBs should
CSPH.[215,216] Although rectal varices appear to have be considered for prevention of rebleeding and
low bleeding rates, small intestinal varices (resulting from decompensation. These patients should be
previous intestinal operation) may exhibit high rates of investigated for the presence of portal vein
bleeding and associated mortality.[216] Few systematic thrombosis.
data exist for the management of patients with these 41. Patients with high-risk cardiofundal (GOV2 or
varices, and the management principles and approaches IGV1) varices ( ≥ 10 mm, red wale signs, CTP
for GV should generally be applied. Surgical manage- class B/C) who have contraindications or
ment is sometimes required in patients with compen- intolerance to NSBBs may be considered for
sated cirrhosis for stomal and small bowel varices with primary prophylaxis with endoscopic
bleeding refractory to NSBB and transvenous therapy. cyanoacrylate injection (ECI).
42. Neither TIPS nor BRTO (or related obliterative
Prevention of bleeding techniques) are recommended to prevent first
hemorrhage in patients with fundal varices that
Patients with compensated cirrhosis with GV who have not bled.
have not experienced acute hemorrhage do have
CSPH and should be evaluated for NSBB therapy with
a goal of preventing rebleeding and
decompensation.[4] The role of primary endoscopic or Management of initial and recurrent
endovascular prophylaxis (TIPS, balloon-occluded bleeding
retrograde transvenous obliteration [BRTO]) to prevent
first hemorrhage in cardiofundal varices remains The initial management of acute gastric or ectopic variceal
unclear because there are a few studies that include bleeding should follow the guidance for acute esophageal
a very low numbers of participants[207,217,218] (Supple- variceal bleeding (see Section V.E and Figure 4). Once
mental Table 1, http://links.lww.com/HEP/I69). One endoscopy confirms the presence of bleeding
RCT showed that the use of cyanoacrylate injection is cardiofundal or ectopic varices, the next management
superior compared with NSBBs to prevent a first steps will be determined by center expertise and the
bleeding episode in patients with cardiofundal varices patient’s vascular anatomy based on cross-sectional
≥ 10 mm in a population that included adults and imaging. If local expertise in the management of
children with compensated and decompensated cir- bleeding GV is not available, the patient should be
rhosis; however, no survival benefit was referred to a tertiary care center. If the initial control of
demonstrated.[207] Performance of endovascular pro- bleeding is not achieved, balloon tamponade preferentially
cedures is feasible to prevent initial hemorrhage in using the Linton-Nachlas or gastric balloon of the
cardiofundal varices and has been reported effective Minnesota tube can be used as a bridge to definite
in case series[217,218]; however, because of the overall therapy. Various endoscopic and endovascular options
paucity of data and relatively high incidence of portal are available including ECI, endoscopic cyanoacrylate
hypertensive complications after BRTO,[219] no formal with endoscopic coiling, endoscopic band ligation, BRTO
recommendations regarding primary prophylaxis using (including variants such as mBRTO, balloon-occluded
endoscopic or endovascular therapy can be made at antegrade transvenous obliteration, and PARTO), and
present. TIPS; please refer to the recent AASLD Practice
Ectopic varices, referring to varices located outside Guidance related to TIPS and endovascular therapy for
of the esophagus and proximal stomach, such as IGV2, variceal hemorrhage for detailed descriptions of technical
duodenal, jejunal, rectal or stomal sites, are uncommon aspects and risks of these approaches.[219]
but can cause substantial bleeding. Similar to GV, Multidisciplinary (hepatology, interventional endoscopy,
ectopic varices more commonly occur with prehepatic interventional radiology) assessment and management of
PH than cirrhosis, often triggered by complications of an patients is recommended.
abdominal operation. Data regarding management are Endoscopic adhesive glue injection, most commonly
limited to case series. No formal recommendations using cyanoacrylate (ECI) (not FDA approved in the
except for use of NSBB for CSPH can be suggested to United States for this indication) and often augmented
prevent initial hemorrhage. with coil embolization, can achieve effective results for
1198
| HEPATOLOGY
initial hemostasis[220–223] with success rates as high as varices should be accompanied by simultaneous
87%–100%, mostly in small series (Supplemental collateral obliteration or embolization.[219,229] See a
Table 3, http://links.lww.com/HEP/I69). EVL is a thera- suggested management algorithm (Figure 4) for
peutic option with low/moderate rates of bleeding bleeding GV management; please refer to Abraldes
control (45%–93%)[221,222]; however, rebleeding rates et al.[219] for details of these techniques.
are higher with EVL compared with glue.[224] Thus, EVL Data around the prevention of rebleeding cardiofundal
should only be performed if no other options are readily or ectopic varices are limited to small randomized trials
available and if the site of rupture (high-risk red signs or and prospective single center cohorts. Overall rebleeding
platelet plug) is visualized and the varices can be rates range from <10% to as high as 54%.[230–238] Similar
completely suctioned into the banding cap. Use of to esophageal variceal bleeding, a combination of a local
balloon occlusion retrograde transvenous variceal therapy (endoscopic or endovascular) and portal pres-
obliteration and related endovascular approaches sure reduction with NSBB are recommended, although
(e.g., BRTO, balloon-occluded antegrade transvenous the beneficial effects of NSBB in the setting of secondary
obliteration, coil-assisted retrograde transvenous oblit- prophylaxis of rebleeding of GV have not been specif-
eration, etc.; please refer to Abraldes et al.[219] for ically studied[30]; NSBB are not required after TIPS
details of these techniques), in which portosystemic placement if portosystemic gradient is reduced to under
collaterals are occluded angiographically through spon- 12 mm Hg. Several endoscopic or endovascular options
taneous splenorenal (or similar) shunts, has shown to are available for prevention of rebleeding, and the
be a successful approach in case series for manage- decision should be taken on a case-by-case basis in a
ment of acute cardiofundal variceal bleeding.[223] How- multidisciplinary setting depending on the characteristics
ever, BRTO and similar obliterative therapies can be of the patient and local expertise[219] and per recent
associated with an increased incidence of ascites and AASLD guidance.[219] ECI with or without endoscopic
bleeding from esophageal varices,[219] although in ultrasound guidance and with or without concomitant use
others, obliterative therapy will improve liver function of coils has been shown to be effective on prevention of
and reduce encephalopathy by redirecting portal flow rebleeding (Supplemental Table 2, http://links.lww.com/
toward the liver. The selection between TIPS or HEP/I69).[221,234,235,238–243] It has been suggested to
obliterative therapy should be based on patient charac- repeat ECI every 2–4 weeks until obliteration. After initial
teristics and local expertise.[219] TIPS may be preferred obliteration, repeat surveillance endoscopy should be
with preserved liver function (MELD-sodium [MELDNa] performed within 3–6 months and thereafter annually.[205]
< 20) in the presence of large esophageal varices, Use of transvenous obliteration (BRTO and technical
significant ascites, and portal vein thrombosis and the variants) has demonstrated lower rebleeding rates, fewer
absence of HE. BRTO may be preferred in patients with hospitalizations, and lower cost compared with ECI in a
HE, MELDNa > 20, or Freiburg Index of Post-TIPS recently published RCT that included 64 patients with
Survival (FIPS) > 0.92.[225–227] Anatomic considerations cirrhosis; however, no survival benefit was observed.[234]
may also guide the choice of TIPS versus retrograde A meta-analysis of observational studies suggests that
transvenous obliteration.[219] BRTO is associated with lower rebleeding rates than
In the event that bleeding cannot be initially TIPS at least in limited follow-up.[244] Importantly,
controlled with medical therapy, EVL, glue and/or patients who underwent transvenous obliteration had
transvenous obliteration, salvage TIPS creation is significantly less encephalopathy than those with TIPS
highly effective for initial bleed control with over 90% creation.[244,245] Because of the advantage of TIPS in
success rate in non-prehepatic PH[228] at the cost of terms of ascites control, the best use of retrograde
increased risks of HE and hepatic functional decline transvenous obliteration alone (without concurrent TIPS)
associated with this procedure. Once initial bleeding is for control of bleeding or prevention of rebleeding in
control is achieved, management follows the same patients with gastric or ectopic varices because of
rules as for esophageal varices. Patients with CTP prehepatic PH, because these patients usually do not
score 7–13 points with active bleeding on endoscopy develop ascites.[244,246,247] TIPS creation is associated
can be considered for preemptive TIPS creation,[181] with comparable or lower rebleeding rates than ECI but
even in the setting of acute-on-chronic liver failure[43]; it with higher rates of HE and similar survival
should be noted, however, that the initial trials of outcomes.[236,248] Concurrent variceal obliteration at the
preemptive TIPS only included patients with esopha- time of TIPS creation further reduces the risk of
geal varices[181] and the specific role of preemptive rebleeding as well as decreasing the risk of
TIPS in gastric and ectopic varices has only being HE.[229,236,244,245,246,249] Finally, a special consideration
studied in an RCT so far with findings quite similar to applies to patients with gastric and ectopic varices as a
those of early TIPS for esophageal varices. Because consequence of isolated splenic vein thrombosis. In
patients with GV typically bleed at lower pressures and these cases of “left-sided portal hypertension,” splenec-
the GV system can compete with the portal vein for tomy, splenic vein stenting,[250] and splenic artery
blood flow,[210] TIPS placement for gastric or ectopic embolization[251] should be considered.
| 1199
Bleeding and prevention of rebleeding from ectopic capillary ectasia.[262,263] Several clinical grading systems
varices should be managed similarly to esophageal and have been proposed to identify features associated with
gastric varices. Data for clear beneficial approaches for high or low risk of complications, including the New Italian
these rare cases remain limited to small retrospective Endoscopic Club (NIEC) and Baveno III systems[264,265]
cohorts.[216,252–254] Endoscopic therapy can be effective, (Table 6). Consensus among grading systems is 1) that
and several reports have shown adequate bleeding the presence of intramucosal hemorrhage (cherry red
control when using endovascular embolization of the spots, black-brown spots, or red point lesions)
feeding vessel with or without a TIPS.[255–261] differentiates severe from mild PHG with moderate
correlation with clinical events during follow-up and 2)
that concomitant gastric antral vascular ectastia (GAVE)
confers higher risk of hemorrhage. The prevalence of PHG
43. Initial management of bleeding gastric or
among patients with compensated cirrhosis ranges from

ectopic varices should be identical to the 49% to 80%,[266–268] with lower prevalence in patients
management of bleeding esophageal varices, without varices (11%)[269] or small varices (35%)[269]
including vasoactive therapy, antimicrobials, relative to those with medium or large varices (80%–
conservative transfusion strategy, and 97%).[268] The development of PHG usually requires the
endoscopic evaluation, within 12 hours. presence of CSPH.[270,271] During longitudinal follow-up of
44. Patients with bleeding gastric or ectopic patients with cirrhosis, progression of PHG is frequently,
varices should have contrast-enhanced cross- and regression more rarely, observed. For instance, in the
sectional imaging to define the anatomy of HALT-C study, 97/170 (57%) patients with cirrhosis
portosystemic collaterals or presence of without PHG at baseline developed PHG, and 115/174
venous thrombosis that would guide therapy. (66%) with baseline PHG exhibited worsening grade over
4 years of clinical follow-up[272]; the presence of varices
45. In patients with acute hemorrhage from gastric and/or CTP class B/C cirrhosis are the strongest predictors
(GOV2/IGV1) or ectopic varices, either of progression.[266,268,269] Additionally, worsening of PHG
endoscopic cyanoacrylate therapy, TIPS, or features can be observed transiently after sclerotherapy or
retrograde transvenous variceal embolization/ ligation of esophageal varices,[273,274] correlating with
obliteration can be considered first-line options. poorer clinical outcomes.[266]
Retrograde obliteration is preferred when TIPS The primary sequelae of PHG are acute and chronic
is contraindicated. hemorrhage. Acute bleeding from PHG is uncommon,
46. In patients who underwent ECI as the main occurring in 2.5%–5%[266,268,269] of cases. Although
therapy, the addition of NSBBs is spontaneous cessation occurs in over half of cases with
recommended to prevent rebleeding, in supportive care, low quality data support the use of
absence of contraindications. Additionally, intravenous octreotide, somatostatin, or terlipressin as a
repeat endoscopic treatment at intervals every safe initial therapy to accelerate resolution and reduce
2–4 weeks until obliteration and long-term need for transfusion.[275,276] Acute administration of
surveillance should be performed. NSBBs reduces gastric hyperemia[277,278] and may also
attenuate bleeding in acute PHG hemorrhage.[279] Most
47. Patients with bleeding GV caused by isolated prospective studies suggest a potential prophylactic role
splenic vein thrombosis should be evaluated for reduction of first or recurrent acute bleeding from PHG
for splenectomy, splenic vein stenting, or with NSBBs[274,279–282] after exclusion of Helicobacter
splenic artery embolization. pylori as an alternative cause of mucosal granularity.[283]
Chronic blood loss, typically defined as a 2 g/dL
reduction in hemoglobin over a 6-month interval, occurs
more commonly than acute bleeding, present in up to
4%–12% of cases.[269,284] An RCT showed a clear
ADDITIONAL TOPIC AREAS FOR benefit from propranolol in preventing recurrent bleed-
GUIDANCE ing from PHG[282]. Recent nonrandomized data suggest
that argon plasma coagulation may also attenuate
Portal gastropathy chronic blood loss with chronic PHG bleeding.[285–287]
A small cases series documented some response to
PHG and/or portal enteropathy, characterized by a “snake- PHG versus GAVE-related acute bleeding with hemo-
skin” mosaic mucosal pattern with variable degrees of static spray.[288] To be expected, case series of
intraepithelial hemorrhage, is a common endoscopic portocaval shunts[289] and TIPS[290] suggest high rates
observation in cirrhosis. The condition results from of bleeding control with portosystemic decompression.
increased portal pressure and submucosal vascular PH-related polyps can be found in the gastric antrum
hyperemia resulting in associated mucosal venous and and occasionally in the duodenum in approximately 1%–
1200
| HEPATOLOGY
10% of patients with cirrhosis, are predominantly hyper- to be increased in the presence of portal vein
plastic, and carry negligible risk of malignant thrombosis.[295–297] Although recent pivotal trials for
transformation.[291,292] PH-related polyps can contribute medications with anti–vascular endothelial growth factor
to chronic gastrointestinal bleeding in patients with properties for advanced HCC have required endoscopy
cirrhosis, which may respond to NSBB or TIPS. Routine within 6 months of enrollment to identify and treat high-
biopsy of PH-related polyps should be discouraged risk varices,[298,299] recent data suggest a poor correla-
because of the benign nature and risk of significant tion between endoscopic findings and variceal bleeding
bleeding from feeding vessels deep within the submucosa. and no benefit of EBL over NSBB prophylaxis.[295]
Among patients with acute variceal bleeding in HCC,
rebleeding rates are increased relative to patients
Guidance statements: without HCC but secondary prophylaxis does signifi-
48. Patients with greater than mild PHG should be cantly reduce this risk.[300]
presumed to have CSPH and should therefore
be considered for prophylactic NSBB to Recommendation:
prevent decompensation; this intervention may
52. Prevention and treatment of AVH and hepatic
also prevent hemorrhagic complications or
decompensation in patients with HCC should
iron-deficiency anemia from severe PHG.
follow the same principles as those for patients
49. In acute bleeding from severe PHG, vasoactive without HCC.
therapy (e.g., somatostatin, somatostatin
53. In the absence of contraindications, NSBB
analogs such as octreotide, or terlipressin if
therapy is recommended for the primary
available; see Table 5) for 2–5 days at doses
prophylaxis for VH and prevention of
used for variceal bleeding should be
decompensation in patients with HCC with
considered.
CSPH (including varices).
50. NSBB are recommended to prevent rebleeding
54. In the presence of occlusive bland or malignant
from PHG and PH-related polyps.
PVT, upper endoscopy is recommended to
51. If bleeding from PHG becomes transfusion- investigate the presence of gastroesophageal
dependent despite NSBB, TIPS placement varices. If varices are detected, NSBB or
should be considered. endoscopic band ligation are recommended;
preference is given to NSBB (including
carvedilol) because of benefits beyond
prevention of variceal hemorrhage.
Varices in HCC
Gastrointestinal bleeding is a known complication of

anti–vascular endothelial growth factor therapies, in- PH in pregnancy
cluding bevacizumab[293] and tyrosine kinase
inhibitors.[294] Variceal hemorrhage is an infrequent Few data exist to guide systematic recommendations
complication[295] but in most (but not all) series appears regarding the management of varices in cirrhotic PH in
pregnancy. AASLD guidance recommends that all
patients with cirrhosis or noncirrhotic PH planning
TABLE 6 Baveno III classification of portal hypertensive pregnancy undergo upper endoscopy within 1 year of
gastropathy conception[301]; unscreened patients should undergo
Feature Score
EGD early in the second trimester. Primary prophy-
laxis with NSBB or EBL for medium and large varices
Mucosal mosaic pattern
are recommended in pregnant patients with prefer-
Mild 1
ence for EBL in the presence of cherry red spots or red
Severe 2 wale signs.[301] In the setting of AVH, terlipressin
Red markings should be avoided because of stimulation of uterine
Isolated 1 contraction, but somatostatin or octreotide may be
Confluent 2 used. Case series exist documenting utilization of
Gastric antral vascular ectasia (GAVE) band ligation[302] and TIPS[303] for secondary prophy-
Absent 1 laxis or to control refractory variceal hemorrhage in
Present 2 pregnancy. Weak evidence suggests that carvedilol
results in lesser fetal growth retardation in pregnancy
Note: Mild PHG ≤ 3, severe PHG ≥ 4.
| 1201
relative to propranolol when used for cardiac nonhepatic operation. A retrospective propensity-
indications.[304] matched study including a small number of patients
with preoperative TIPS undergoing visceral and non-
visceral operation identified a reduction of acute-on-
chronic liver failure and death within 90 days of
55. All patients with cirrhosis or noncirrhotic PH operation.[308] In the absence of prospective studies,
planning pregnancy should undergo upper TIPS can be considered in patients on a case-by-case
endoscopy within 1 year of conception. basis weighing the potential surgical benefits of TIPS
56. Unscreened pregnant patients with cirrhosis or with potential increased risk of HE and of worsening
noncirrhotic PH should undergo EGD early in liver failure.
the second trimester.
Guidance statement:
58. Preoperative TIPS can be considered on a
case-by-case basis after careful consideration
Endoscopy before TEE of potential surgical benefits relative to
potential harms related to the procedure
There is no evidence that TEE in patients with varices (encephalopathy, worsening of liver failure).
poses a significant risk of inducing variceal hemorrhage
or that routine upper endoscopy prior to TEE significantly
impacts patient outcomes.[305–307] As such, routine upper
endoscopy prior to TEE is not recommended.
C O N C L U S I O N S A N D A R E A S FO R
Guidance statement:
FUTURE RESEARCH (BOX 4)
57. Routine upper endoscopy prior to TEE in The ability to noninvasively identify patients at high risk
patients with cirrhosis is not recommended. for decompensation and evidence that decompensation
rates can be decreased with therapy enable a paradigm
shift toward prevention of decompensation through
NSBBs, disease control, and lifestyle modification.
Once decompensated, improved understanding of
Preoperative TIPS prior to nonhepatic resuscitation and the role of preemptive TIPS should
operation improve the survival of patients with AVH. It is expected
that advances in knowledge on the mechanisms
Few data, and none emerging from RCTs, exist to involved in increased hepatic vascular tone and disease
confirm a benefit or risk-stratify patients with PH who progression/regression will result soon in RCTs of new
may benefit from preoperative TIPS for elective drugs for PH in patients with cirrhosis.
BOX 4 Key areas of future research
(a) Prospective validation of the “rule of 5” for the noninvasive selection of candidates for early initiation of nonselective beta-blockers
(NSBBs) to prevent clinical decompensation and avoid screening endoscopy
(b) Systematic and cross-platform validation of cutpoints for magnetic resonance elastography, two-dimensional shear wave elastography,
and point shear wave elastography for estimation of presence of clinically significant portal hypertension and high-risk varices
(c) Identification and validation of noninvasive modalities to monitor 10%–20% changes in HVPG
(d) Confirmation of clinical, Noninvasive Liver Disease Assessment (NILDA), and/or HVPG thresholds for clinical recompensation after
which screening endoscopy or NSBB therapy is no longer required, allowing de-escalation of monitoring and treatment for portal
hypertension
(e) External validation of the PREDESCI trial in additional populations (patients with NASH)
(f) Definition of patients with portal hypertension who might benefit from an earlier decision for TIPS (i.e., after first bleeding; before major
operation)
(g) Quantification of the benefit from nutritional intervention in patients with cirrhosis and sarcopenia and/or frailty for prevention of first or
further decompensation and/or improvement in survival
(h) Confirmation of the safety and effectiveness of statins in improving survival and/or preventing decompensation, further decompensation,
and acute-on-chronic liver failure when used alone or coadministered with NSBBs, rifaximin, or other treatments
(i) Larger prospective studies of self-expanding esophageal stents to confirm role and refine utilization in acute variceal hemorrhage
1202
| HEPATOLOGY
AUTHOR CONTRIBUTIONS Association for the Study of Liver Diseases. Hepatology. 2017;
Kaplan David E.: Conceptualization, Writing - Original 65:310–35.
Draft, Writing - Review & Editing, Visualization, 2. Garcia-Tsao G, Sanyal AJ, Grace ND, Carey W. Practice
Guidelines Committee of the American Association for the
Supervision, Project administration; Cristina Ripoll: Study of Liver Diseases, Practice Parameters Committee of the
Writing - Original Draft, Writing: Review & Editing, American College of Gastroenterology. Prevention and man-
Visualization; Maja Thiele: Writing - Original Draft, agement of gastroesophageal varices and variceal hemorrhage
Writing - Review & Editing, Visualization; Brett E. in cirrhosis. Hepatology. 2007;46:922–38.
Fortune - Writing - Original Draft, Writing - Review & 3. de Franchis R, Bosch J, Garcia-Tsao G, Reiberger T, Ripoll C,
on behalf of the Baveno VII Faculty. Baveno VII - renewing
Editing, Visualization; Douglas A. Simonetto: Writing - consensus in portal hypertension. J Hepatol. 2022;76:959–74.
Original Draft, Writing - Review & Editing, Visualiza- 4. Villanueva C, Albillos A, Genescà J, Garcia-Pagan JC, Calleja
tion, Guadalupe Garcia-Tsao: Writing - Original Draft, JL, Aracil C, et al. β blockers to prevent decompensation of
Writing - Review & Editing, Visualization; Jaime cirrhosis in patients with clinically significant portal hypertension
(PREDESCI): A randomised, double-blind, placebo-controlled,
Bosch: Conceptualization, Writing - Original Draft,
multicentre trial. Lancet. 2019;393:1597–608.
Writing - Review & Editing, Visualization, Supervision, 5. Biggins SW, Angeli P, Garcia-Tsao G, Gines P, Ling SC, Nadim
Project administration. MK, et al. Diagnosis, evaluation, and management of ascites,
spontaneous bacterial peritonitis and hepatorenal syndrome:
ACKNOWLEDGMENT 2021 Practice Guidance by the American Association for the
The authors are grateful for the valuable contributions of Study of Liver Diseases. Hepatology. 2021;74:1014–48.
6. Northup PG, Garcia-Pagan JC, Garcia-Tsao G, Intagliata NM,
the AASLD Practice Guideline Committee (PGC), Superina RA, Roberts LN, et al. Vascular liver disorders, portal
particularly David S. Goldberg, MD, MSCE, Scott W. vein thrombosis, and procedural bleeding in patients with liver
Biggins, MD, MAS, FAASLD, Elizabeth C. Verna (Chair) disease: 2020 Practice Guidance by the American Association
and Cynthia Levy (Vice Chair). The PGC Review group for the Study of Liver Diseases. Hepatology. 2021;73:366–413.
7. Lee EW, Eghtesad B, Garcia-Tsao G, Haskal ZJ, Hernandez-
members include Archita Parikh Desai, Cynthia Levy,
Gea V, Jalaeian H, et al. AASLD Practice Guidance on the use
Ashwani K. Singal, Elizabeth Rand, Nadia Ovchinsky, of TIPS, variceal embolization, and retrograde transvenous
Puneeta Tandon, and Elizabeth C. Verna. obliteration in the management of variceal hemorrhage.
Hepatology. 2023. doi: 10.1097/HEP.0000000000000530.
F U N D I N G IN F O R M A T I O N Epub ahead of print.
Funding for the development of this Practice Guidance 8. Luca A, Cirera I, García-Pagán JC, Feu F, Pizcueta P, Bosch J,
et al. Hemodynamic effects of acute changes in intra-abdominal
was provided by the AASLD. pressure in patients with cirrhosis. Gastroenterology. 1993;104:
222–7.
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Jamie Bosch receives lecture fees from Gore and Shah VH, et al. Prioritization of therapeutic targets and trial
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Healthcare, and GSK. Brett E. Fortune consults for W.L 10. D’Amico G, Pasta L, Morabito A, D’Amico M, Caltagirone M,
Gores and Associates. Douglas A. Simonetto consults Malizia G, et al. Competing risks and prognostic stages of
for Mallinckrodt and BioVie. The remaining authors cirrhosis: A 25-year inception cohort study of 494 patients.
have nothing to report. Aliment Pharmacol Ther. 2014;39:1180–93.
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Received: 16 October 2023 | Accepted: 16 October 2023

and varices in cirrhosis

P U R P O S E AN D S C O P E Guidance (Box 1) therefore relate to ,2

1180 | www.hepjournal.com Hepatology. 2024;79:1180–1211

not be used for clinical decision-making without

Reductions in portal pressure induced by pharmaco- hepatitis

TABLE 2 Therapeutic targets in portal hypertension

Indefinitely or until TIPS

Healthy lifestyle Alcohol elimination

ascites: 160 mg/day

12.5 mg/day (higher

320 mg/day; with

160 mg/day; with

PARTO,esophageal stents, balloon

Abbreviations: SBP, spontaneous bacterial peritonitis; HR, heart rate.

Abbreviations: AIH, autoimmune hepatitis; BRTO, balloon-occluded ret-

rograde transvenous obliteration; PARTO, plug occluded retrograde

Above plus decreased intrahepatic

vascular resistance; caused by

1. Carvedilol is recommended as the preferred

dose of carvedilol may be further increased to

address nonhepatic indications.

percutaneous access, portal pressure is more com-

monly determined indirectly by measuring the liver

occlude the hepatic vein lumen is achieved either by

catheter in a large hepatic vein, the latter being

considered the standard approach.[42,43] After occlusion,

the pressure measured in the static column of blood

cirrhosis intersinusoidal communications are closed

Death, LT, hospitalizations

to the portal vein pressure. The difference between

WHVP and unwedged “free hepatic vein pressure”

(FHVP; measured with the tip of the catheter introduced

approximating the portacaval pressure gradient.

Accuracy of HVPG measurements can be increased

obtaining triplicate measurements; and (3) by following

Compensated cirrhosis with CSPH (HVPG)

several simple measurement conventions (Box 2).[42,43]

HVPG provides valuable prognostic information in

compensated and decompensated cirrhosis at

(such as beta-blockers),[45–48] after elimination of the

for HCC,[51] and prior to any major operation in patients

HVPG measurement does not accurately estimate

diseases, and portosinusoidal vascular disorder (previ-

ously referred to as idiopathic PH or noncirrhotic

or periportal sclerosis as main histological

with NASH[53]; HVPG values, changes in HVPG, and

CSPH do retain prognostic significance among patients

gold standard to assess the presence and quantify the

degree of PH,[42] it is moderately invasive and carries

small risks of injury related to access of the jugular vein,

induction of arrhythmias, and exposure to radiation.[56]

Interpretation of HVPG also requires specific expertise.

BOX 2 ABCs of HVPG measurement

1. Consider the planned approach:

4. Use balloon-tipped catheters of 10–12 mm balloon diameter.

and nonexternally validated, studies have reported

should be paid to imaging evidence indicating develop- Guidance statements:

repeated until all varices are eradicated. Intervals