PREAMBLE
Background and aims
Patients with decompensated cirrhosis with complications have a very poor prognosis
and require careful management. Varices are common complications in patients with
cirrhosis. Although the prognosis of variceal bleeding has improved with recent advances
in diagnosis and treatment, the mortality rate remains 12–22%. Hepatic encephalopathy
(HE) is known to occur in 10–14% of patients with cirrhosis and 16–21% of patients
with decompensated cirrhosis. More than 20% of cirrhotic patients who visit emergency
rooms in Korea present with HE. Therefore, cirrhosis is a serious disease in Korea
and requires specific Korean guidelines for diagnosis, treatment, and prevention.
In 2005, the Korean Association for the Study of the Liver (KASL) enacted a clinical
practice guideline (CPG) for the treatment of cirrhosis complications including ascites,
hepatorenal syndrome, varices, and HE. In 2011, the guidelines for the treatment of
cirrhosis were revised to integrate antifibrotic treatment and update the diagnosis
and treatment advice for variceal bleeding, cirrhotic ascites, and HE. In 2017, the
CPG for liver cirrhosis was revised for ascites and related complications. At this
time, KASL is revising the CPG for liver cirrhosis to address varices and HE following
ascites and related complications. To date, many studies have addressed the prevention
and treatment of gastroesophageal variceal bleeding and HE, and many guidelines have
been based on those studies, but most of them contain foreign data that are difficult
to apply to Korean clinical practice. Therefore, these revised guidelines for the
treatment of varices and HE are offered for Korean practice to reflect the latest
research results and extensive discussions within the revision committee. This guideline
contains the opinions of experts and is intended to be a practical reference for the
care of patients with varices and HE; it is not an absolute standard of care. The
best choices for each patient’s care vary from case to case, and the judgment of the
doctor in charge is important. As medical evidence and new findings accumulate in
the future, these guidelines will require ongoing supplementation and revision. This
guideline may not be modified or altered without permission.
Target population
This guideline discusses patients with varices, HE, and related complications (esophageal
varices [EVs] and bleeding, gastric varices and bleeding, portal hypertensive gastropathy,
covert and overt HE) caused by liver cirrhosis. It is intended for clinicians and
other medical personnel who are in charge of diagnosing and treating patients with
liver cirrhosis. This guideline is also intended to provide practical clinical and
educational information and directions for resident physicians and fellows in training,
practitioners, and their trainers and supervisors.
Development, funding, and revision process
Comprising 14 hepatologists, the Clinical Practice Guideline Committee for Liver Cirrhosis:
Varices, HE, and related complications (the Committee) was organized by the KASL Board
of Executives. Funding for the revisions was provided by KASL. Each committee member
collected and analyzed source data in his or her own field, and the members then wrote
the manuscript together.
Literature review
The Committee selected keywords and questions using PICO (Patient/Problem, Intervention,
Comparison, Outcome) assessments and systematically collected and reviewed international
and domestic literature available in PubMed, MEDLINE, KoreaMed, the Korean Medical
Database, and other databases. In addition to published articles, abstracts of important
meetings published before January 2019 were evaluated.
Levels of evidence and grades of recommendation
The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system
(Table 1) was applied to grade the evidence and recommendations. The levels of evidence
are based on the possibility of change in the estimate of clinical effect by further
research and are described as high (A), moderate (B), or low (C). The recommendations
are also classified as strong (1) or weak (2) by the GRADE system based on the quality
of evidence, the balance between the desirable and undesirable effects of an intervention,
generalizability, and socioeconomic aspects (including cost and availability). Each
recommendation is labeled with the level of relevant evidence (A–C) and corresponding
recommendation grade (1, 2) as follows: A1, A2, B1, B2, C1, C2.
List of key questions
The Committee selected the following key questions about varices, HE, and related
complications to cover in this guideline.
Key varix-related questions
1) How should varices be monitored?
2) Who needs monitoring for varices?
3) How can the development and progression of EVs be prevented?
4) Who needs treatment to prevent initial esophageal variceal bleeding?
5) What is the proper management for preventing initial esophageal variceal bleeding?
6) How can acute esophageal variceal bleeding be diagnosed?
7) What is the appropriate pharmacological treatment for acute esophageal variceal
bleeding?
8) What is the proper endoscopic treatment for acute esophageal variceal bleeding?
9) What are the options for rescue treatment when endoscopic treatment of acute variceal
bleeding fails?
10) What is the primary treatment to prevent EVs from rebleeding?
11) What are the options for rescue treatment when primary treatment to prevent EVs
from rebleeding fails?
12) Who needs treatment to prevent gastric variceal bleeding?
13) What is the proper treatment to prevent gastric variceal bleeding?
14) What is the proper treatment of acute gastric variceal bleeding?
15) What is the primary treatment to prevent gastric varices from rebleeding?
16) How should portal hypertensive gastropathy be classified?
17) How should portal hypertensive gastropathy be managed?
Key HE-related questions
1) How should HE be diagnosed and classified?
2) How should overt HE be defined and diagnosed?
3) What are the precipitating factors of overt HE?
4) What differential diagnoses should be considered in diagnosing overt HE?
5) Is the measurement of serum ammonia helpful in diagnosing overt HE?
6) Is radiologic image evaluation of the central nervous system helpful in diagnosing
overt HE?
7) What neurophysiological or neuropsychological tests are clinically necessary to
diagnose overt HE?
8) How should the acute phase of overt HE be treated, and how should recurrence be
prevented?
9) Are branched chain amino acids helpful in treating and preventing overt HE?
10) Is L-ornithine-L-aspartate (LOLA) helpful in treating and preventing overt HE?
11) Is proper education helpful in preventing the recurrence of and readmission for
HE?
12) How should covert HE be defined and diagnosed?
13) What is the clinical significance of covert HE?
14) How should covert HE be treated?
15) How should the quality of life of HE patients be assessed? Does treating HE improve
patient quality of life?
Review of the manuscript and approval process
Each manuscript written by members was reviewed and approved through meetings of the
Committee. An updated manuscript was reviewed at a meeting of the advisory board and
opened to a public hearing attended by KASL members, members of related organizations,
and representatives from patient associations. The final manuscript was approved by
the KASL Board of Executives.
Release of the guidelines and plan for updates
The revised guideline (The KASL Clinical Practice Guidelines for Liver Cirrhosis:
Varices, Hepatic Encephalopathy and Related Complications) was released at a KASL
meeting on 22 June 2019. The Korean version of the guideline is available on the KASL
website (http://www.kasl.org).
VARICES
Varices are a frequent complication of liver cirrhosis and a leading cause of mortality
in patients with liver cirrhosis. Varices were present in 52.2% of patients who received
endoscopy for variceal screening [1], and the incidence of varices was significantly
higher in patients with Child-Pugh class B/C than in those with Child-Pugh class A
(35–43% vs. 48–72%) [1,2]. Portal hypertension, which is the most common complication
of liver cirrhosis, is the main determinant in the development of varices. Increased
intrahepatic vascular resistance to portal flow leads to the development of portal
hypertension, which is aggravated by splanchnic vasodilatation and an increase in
portal blood flow caused by hyperdynamic circulation [3-5]. When the portal pressure
increases above a threshold, collaterals develop at the site of communication between
the portal and systemic circulation, of which varices are the most important. With
the aggravation of portal hypertension, the collaterals grow and eventually rupture.
Bleeding from varices is a major complication of portal hypertension and a leading
cause of mortality in patients with liver cirrhosis. Therefore, preventing variceal
development and progression, preventing bleeding from varices, appropriately managing
acute bleeding from varices, and preventing variceal rebleeding are critical in patients
with liver cirrhosis.
The incidence of varices in cirrhotic patients without varices at baseline is 5–9%
at 1 year and 14–17% at 2 years [6,7]. The main risk factor for variceal development
in these patients is a higher hepatic venous pressure gradient (HVPG) [6]. Small EVs
often progress to large varices; the incidence of progression from small to large
EVs is 12% at 1 year and 25% at 2 years. The independent risk factors of EV progression
are alcoholic cirrhosis, decompensated disease, and splenomegaly [7]. The 1-year incidence
of variceal bleeding in patients with cirrhosis and varices without a previous history
of bleeding is approximately 12% (5% for small varices and 15% for large varices),
and the main risk factors of bleeding are larger varices, the presence of redness
over the varices, and decompensated disease [8]. Although the mortality rate has decreased
significantly during the past several decades thanks to improvements in diagnostic
and therapeutic modalities [9,10], it remains as high as 12–22% [11-14]. In addition,
rebleeding is frequent, up to 60% within 1 year, without appropriate treatment to
prevent it [15].
Surveillance of varices
Endoscopic surveillance of varices
Given the high prevalence of varices and poor prognosis with variceal bleeding, monitoring
varices is important in patients with liver cirrhosis. Therefore, upon first diagnosis
with liver cirrhosis, endoscopy should be performed to look for varices and assess
the risk of bleeding. Diagnosis of liver cirrhosis is not difficult in patients with
decompensated liver cirrhosis accompanied by ascites or variceal bleeding, but a liver
biopsy is needed to diagnose patients with compensated cirrhosis who have no clinical
symptoms or signs. However, liver biopsy is an invasive procedure with a risk of serious
complications [16]. Furthermore, doubt has been cast on the accuracy of liver biopsy
because of the risk of sampling errors [17,18] and intra- and interobserver variability
[18,19].
Liver cirrhosis can disappear with appropriate treatment of the underlying liver disease
[20,21], though portal hypertension can accompany the severe stage of fibrosis (F3)
[22,23]. Various practice guidelines recommend surveillance for hepatocellular carcinoma
in patients with liver fibrosis, even before the development of cirrhosis [24,25].
Therefore, the alternative term compensated advanced chronic liver disease (cACLD)
has been proposed for patients with severe fibrosis (F3) and compensated liver cirrhosis
to better reflect that the spectrum of severe fibrosis and cirrhosis is a continuum
in asymptomatic patients and that distinguishing between these two conditions is often
clinically impossible [26]. A liver stiffness value, measured by transient elastography,
of <10 kPa can rule out cACLD, and a value between 10 and 15 kPa is suggestive of
cACLD but needs further tests for confirmation. A value >15 kPa is highly suggestive
of cACLD [26]. Endoscopic surveillance of all patients with cACLD can cause problems,
such as an increase in medical costs due to an increase in unnecessary tests. Therefore,
noninvasive screening tests have been proposed for patients with EVs, especially those
whose EVs have a high risk of bleeding, to reduce unnecessary endoscopic surveillance.
The Baveno VI criteria suggest that endoscopic surveillance can be avoided in cACLD
patients with a liver stiffness <20 kPa and a platelet count >150×109/L because they
are at very low risk for varices that need to be treated [26]. Augustin et al. [27]
expanded the Baveno VI criteria to say that endoscopic surveillance can be avoided
in cACLD patients with liver stiffness <25 kPa and a platelet count >110×109/L. However,
considering that noninvasive screening for varices that need to be treated is not
particularly reliable [28,29] and endoscopy is more easily accessed in Korea than
in Western countries, we do not deem screening by noninvasive test to be useful in
Korea.
Surveillance of EVs
The incidence of EV development in cirrhotic patients without varices is 5–9% at 1
year and 14–17% at 2 years [6,7]. Small EVs progress to large varices at the rate
of 12% after 1 year and 25% after 2 years [7]. Therefore, endoscopic surveillance
should be performed more frequently in patients with small EVs than in those without
EVs. In addition, because the type of underlying liver disease (e.g., alcoholic cirrhosis)
and liver function (e.g., decompensated cirrhosis) are risk factors for the progression
of EVs, they should be taken into account when determining the surveillance interval.
Endoscopic surveillance should be performed at 2–3-year intervals in patients with
compensated liver cirrhosis and at 1–2-year intervals in those with decompensated
liver cirrhosis [30,31].
EVs can be classified as large or small according to their size, with a breakpoint
at 5 mm in diameter [32], or they can be classified as F1 (linearly dilated, small
and straight varices), F2 (beady varices, tortuous and occupying less than one third
of the esophageal lumen), or F3(nodular varices, large and occupying more than one
third of the esophageal lumen) [33]. However, because the F2 and F3 classifications
are fairly subjective and prophylactic treatment is recommended both for F2 and F3,
F1 is usually classified as small, and F2 and F3 are classified together as large.
[Recommendations]
1. In patients diagnosed with liver cirrhosis, screening endoscopy is recommended
to determine the presence of varices and assess the risk of bleeding. (A1)
2. In endoscopy, EVs are classified as small (F1) and large (F2 or F3), and the presence
of redness should be evaluated. (B1)
3. To identif y the development and progression of EVs, endoscopic surveillance should
be performed at 2–3-year-intervals in patients with compensated liver cirrhosis and
at 1–2-year intervals in those with decompensated liver cirrhosis. The frequency of
endoscopic surveillance could be modified according to the type and severity of underlying
liver disease. (B1)
Preventing the formation and progression of EVs
Appropriate treatment for the underlying liver disease can improve liver fibrosis,
which could improve portal hypertension and prevent the development of complications.
In patients with hepatitis B virus-related liver cirrhosis, the cirrhosis disappeared
from the liver biopsy reports of 74% after 5 years of treatment with tenofovir disoproxil
fumarate [20], and in a meta-analysis, hepatic histologic improvement was observed
in chronic hepatitis C patients treated with pegylated interferon±ribavirin [34].
In an earlier study of patients with nonalcoholic fatty liver disease, the degree
of weight loss correlated with the degree of histologic improvement [35]. Furthermore,
the incidence of EVs was significantly lower in patients with a sustained virologic
response (SVR) to pegylated interferon+ribavirin treatment than in those without an
SVR [36-38]. In a recent study, portal pressure was significantly lower in patients
with an SVR to direct-acting agents than in those without an SVR in patients with
hepatitis C virus-related liver cirrhosis [39].
Because the development of GEVs is a direct consequence of portal hypertension, reducing
the portal pressure through the use of nonselective beta-blockers (NSBBs) from the
early stage of liver cirrhosis could theoretically ameliorate the formation of GEVs.
However, a placebo-controlled study to determine whether NSBBs could prevent the formation
of varices in 213 patients with cirrhosis and portal hypertension without GEVs, the
incidence of varices or bleeding from varices did not differ between timolol group
and the placebo group (39% vs. 40%, P=0.89), and serious adverse events developed
more frequently in the timolol group than the placebo group (18% vs. 6%, P=0.006)
[6]. Therefore, the use of NSBBs to prevent the formation of varices is not recommended.
Several studies have evaluated whether NSBBs can prevent or delay the growth of small
varices, and the results conflict. One study found a significant reduction in the
rate of progression to large EVs in the nadolol group compared with the placebo group
in patients with cirrhosis and small EVs (7% vs. 31% at 2 years, 20% vs. 51% at 5
years; P<0.001) [40], but another study showed that propranolol offered no benefit
for the prevention of progression to large varices (23% in the propranolol group vs.
19% in the placebo group, P=0.786), even though the reduction in portal pressure was
significantly greater in the propranolol group [41]. A recent meta-analysis suggests
that NSBBs are not effective in preventing the progression from small to large varices
[42]. Another study found that the incidence of progression to large varices across
24 months was significantly lower in the carvedilol group than the placebo group (20.6%
vs. 38.6%, P=0.04), leading those researchers to suggest that carvedilol is a safe
and effective way to delay the progression of small to large EVs in patients with
cirrhosis [43].
Carvedilol reduces portal pressure by means of an anti-a1-mediated decrease in intrahepatic
resistance and splanchnic vasoconstriction. Because intrahepatic vasoconstriction
is the main pathologic mechanism in the development of portal hypertension during
early-stage liver cirrhosis, it could be more effective than other medications in
preventing the progression of varices in patients with early-stage cirrhosis [44].
However, further studies are needed to confirm the effects of carvedilol.
[Recommendations]
1. Appropriate treatment for the underlying liver disease is recommended to prevent
the formation of EVs. (A1)
2. NSBBs (propranolol and nadolol) are not recommended to prevent the formation of
EVs in cirrhotic patients without EVs. (A1)
3. In patients with small EVs that are not red, NSBBs (propranolol and nadolol) or
carvedilol could be considered to prevent the progression of EVs. (B2)
Prevention of first variceal bleeding in patients with EVs
In patients with liver cirrhosis and EVs, variceal bleeding occurs at a yearly rate
of 5–15% of cases. Active prevention of the first variceal bleeding is indicated in
patients at a high risk of bleeding, such as patients with large varices (F2, F3),
decompensated cirrhosis, or varices with red color signs on endoscopy [8,45].
Prevention of first variceal bleeding in patients with small EVs
In cirrhotic patients with small EVs, the risk of bleeding is low (3% at 2 years and
8% at 4 years) and remains low in patients whose varices remain small at the follow-up
endoscopy, though it increases significantly when the varices become large. An increase
in Child-Pugh score during follow-up appears to be a significant predictor of enlarged
varices and thus an increase in bleeding risk [46]. The prevention of first bleeding
in patients with small EVs depends on their risk of bleeding. Patients with small
varices with red color signs on endoscopy or decompensated cirrhosis have an increased
risk of bleeding and should consider using NSBBs [26,47].
Prevention of first variceal bleeding in patients with large EVs
NSBBs and EVL
Meta-analyses of randomized controlled trials (RCTs) have shown that the use of NSBBs
can prevent first variceal bleeding in cirrhotic patients with large EVs [48,49].
A study comparing NSBBs and EVL as primary prophylaxis in patients with high-risk
EVs found no significant difference between them in bleeding rates (relative risk
[RR], 0.86; 95% confidence interval [CI], 0.55–1.35) [50]. A meta-analysis of RCTs
evaluating the efficacy of EVL and pharmacological therapy in preventing first EV
bleeding in patients with cirrhosis also found no significant difference in the rate
of variceal bleeding between the two groups [51]. Another meta-analysis found that
EVL significantly reduced the rate of first variceal bleeding and severe adverse events
than NSBBs in patients with large EVs [52]. Thus, in most studies, the efficacy of
EVL in preventing first variceal bleeding was similar to that of NSBBs, and in some
studies, the efficacy of EVL was superior to NSBBs. Therefore, either NSBBs or EVL
is recommended for the prevention of first variceal bleeding in patients with large
EVs. The choice of treatment should be based on clinician expertise and patient preference,
characteristics, contraindications, and adverse events [26,47].
Carvedilol
Carvedilol is known to be more effective in reducing portal pressure than propranolol
[53-55]. In a multicenter RCT comparing the efficacy of carvedilol and EVL in preventing
first variceal bleeding in cirrhotic patients with large EVs, carvedilol had lower
rates of first variceal bleeding (10% vs. 23%, P=0.04), but there was no significant
difference in overall mortality or bleeding-related mortality during follow up [56].
In another RCT comparing the efficacy of carvedilol and EVL for primary prophylaxis
of EV bleeding, the carvedilol and EVL groups had comparable variceal bleeding rates
(8.5% vs. 6.9%, P=0.61) [57]. In a study assessing the efficacy of carvedilol, propranolol,
and EVL for the primary prevention of variceal bleeding in patients with large varices,
no significant differences among the groups were found in the risk of bleeding (15.4%
vs. 10.8% vs. 10.2%, P=0.071), but the incidence of adverse events was the highest
in the propranolol group [58]. In studies comparing the efficacy of carvedilol, NSBBs,
and EVL for the primary prevention of EV bleeding, carvedilol was similar to NSBBs
and EVL or superior to EVL. Therefore, carvedilol can also be used to prevent first
variceal bleeding in patients with high-risk EVs.
Combination therapy of EVL and NSBBs
The combination of EVL and NSBBs for the primary prophylaxis of variceal bleeding
could have a synergistic effect from the direct eradication of varices by EVL and
the reduction of portal pressure by NSBBs. Several studies have compared the efficacy
of combination therapy with that of monotherapy based on that hypothesis. In RCTs
comparing EVL plus propranolol with EVL alone for preventing first variceal bleeding
in patients with high-risk EVs, the combination therapy did not show any difference
from EVL alone in first bleed occurrence or mortality during follow up. However, the
recurrence of varices was lower in the combination group than in the EVL alone group
[59,60]. No difference in the rate of first variceal bleeding was also found between
EVL plus nadolol combination therapy and nadolol alone (14% vs. 13%, P=0.90) [61].
However, another study reported that EVL and propranolol combination therapy lowered
the rate of first variceal bleeding compared with propranolol alone (6% vs. 31%, P=0.03)
[62]. Because most studies have shown that EVL and NSBBs combination therapy for the
primary prophylaxis of EV bleeding do not differ in bleeding rate or mortality compared
with monotherapy, combination therapy is generally not recommended. However, some
studies have reported that EVL and NSBBs combination therapy reduced the rate of first
variceal bleeding and variceal recurrence compared with monotherapy. Therefore, combination
therapy can be considered in selected patients. A recent meta-analysis of RCTs showed
that combination therapy with EVL and NSBBs reduced the rate of first variceal bleeding
compared with placebo and isosorbide-5-mononitrate (ISMN) [63].
ISMN
In an RCT of cirrhotic patients with EVs, the ISMN group and propranolol group had
no significant difference in bleeding rate, but the mortality rate during follow up
was higher in the ISMN group (72.3% vs. 47.8% at 6 years, P=0.006) [64]. In a multicenter
RCT comparing EVL, propranolol, and ISMN, the EVL and propranolol groups did not differ
significantly, but the EVL group had a significantly lower rate of first variceal
bleeding than the ISMN group (7.5% vs. 33% at 2 years, P=0.03) [65]. A multicenter
RCT compared propranolol plus placebo with propranolol plus ISMN for the prevention
of EV bleeding. The rate of first variceal bleeding did not differ significantly between
the groups (10.6% vs. 12.5% at 2 years, P>0.05) [66]. Therefore, ISMN alone or in
combination with NSBBs is not recommended for the prevention of first variceal bleeding.
Treatment practices for the prevention of first esophageal variceal bleeding
NSBBs
The advantages of NSBBs include low cost, ease of administration, and not requiring
follow-up endoscopies. Propranolol is started at 20–40 mg twice a day and adjusted
every 2–3 days until the treatment goal (resting heart rate of 55–60 beats per minute)
is achieved. The maximum dose is 320 mg daily in patients without ascites and 160
mg daily in patients with ascites. Nadolol is started at 20–40 mg once a day and adjusted
every 2–3 days until the treatment goal is achieved. The maximum dose is 160 mg daily
in patients without ascites and 80 mg daily in patients with ascites. Systolic blood
pressure should not decrease <90 mmHg [47].
The disadvantages of NSBBs are that about 15% of patients have contraindications to
therapy, and another 15% or so require dose reduction or discontinuation because of
side effects [47]. Contraindications to NSBBs include sinus bradycardia, insulin-dependent
diabetes mellitus, obstructive pulmonary disease, heart failure, aortic valve disease,
second- or third-degree atrioventricular heart block, and peripheral arterial insufficiency
[67]. Side effects of NSBBs include dizziness, fatigue, general weakness, dyspnea,
headache, hypotension, bradycardia, and erectile dysfunction [47,58,66,67]. Discontinuing
NSBBs can increase the risk of variceal bleeding and mortality. Thus, treatment with
NSBBs should be continued indefinitely [68,69]. In patients with contraindications
or discontinuation due to severe side effects or poor compliance with NSBBs, EVL is
recommended [68].
In patients with end-stage liver disease, such as refractory ascites or spontaneous
bacterial peritonitis, the administration of NSBBs has not yet been established. In
cirrhotic patients with refractory ascites, the use of NSBBs can lower arterial pressure,
decrease survival time [70], and increase the risk of paracentesis-induced circulatory
dysfunction [71]. In addition, among patients with cirrhosis and spontaneous bacterial
peritonitis, NSBBs increase the risk of hepatorenal syndrome and acute kidney injury
and reduce survival time [72]. However, other studies have reported that the use of
NSBBs increased or did not affect survival time in cirrhotic patients with refractory
ascites [73,74]. Another study found that treatment with low-dose propranolol (80
mg/day) increased survival time in patients with spontaneous bacterial peritonitis
[75]. The role of NSBBs in patients with refractory ascites or spontaneous bacterial
peritonitis thus remains uncertain, and clinicians must carefully consider the risks
and benefits when deciding whether to administer them. If NSBBs are administered,
thorough monitoring of blood pressure and renal function is necessary, and dose reduction
or discontinuation should be considered in patients who develop low blood pressure
or impaired renal function. Discontinuation of NSBBs can increase the risk of EV bleeding;
thus, if NSBBs are stopped, EVL should be considered [26].
Carvedilol
Adjusting the dose of carvedilol is easier than adjusting the dose of NSBBs because
it is not guided by heart rate. Carvedilol is started at 6.25 mg once a day (or 3.125
mg twice a day), and after 3 days increased to 6.25 mg twice a day. The maximum dose
is 12.5 mg daily. Systolic blood pressure should not be decreased <90 mmHg [47].
EVL
The advantages of EVL are that it can be performed in the same session as screening
endoscopy, and it has few contraindications. The disadvantages of EVL are the side
effects associated with sedation and the risk of causing dysphagia, esophageal ulcerations,
strictures, and bleeding. Although the incidence of side effects is higher with NSBBs,
severe side effects, such as ulcer bleeding at the ligation site, are more likely
to be associated with EVL [47]. Some studies have reported that proton pump inhibitors
(PPIs) significantly reduce the size of post-EVL ulcers or the rate of post-EVL ulcer
bleeding [76-78]. In cirrhotic patients, the long-term use of PPIs can increase the
risk of spontaneous bacterial peritonitis and HE, so PPIs should be used with caution
[79-81]. Meanwhile, because EVL is a local therapy that does not act on the pathophysiology
of portal hypertension, not only is it unable to prevent complications other than
variceal bleeding, but it also requires follow-up endoscopies to assess variceal recurrence,
even after variceal eradication [47], defined as a case in which varices are not seen
or become too small to be ligated. Repeat EVL can be performed at intervals of 2–8
weeks until variceal eradication is achieved. Follow-up endoscopies should be performed
1–6 months after variceal eradication and every 6–12 months thereafter [47,59,82].
[Recommendations]
1. In cirrhotic patients with small EVs that have a high risk of bleeding (decompensated
cirrhosis or red color signs on endoscopy), the use of a NSBBs (propranolol or nadolol)
should be considered to prevent first variceal bleeding. (B1) NSBBs are adjusted every
2–3 days until the resting heart rate reaches 55–60 beats per minute.
2. In cirrhotic patients with large EVs, the use of a NSBBs (propranolol or nadolol),
carvedilol, or EVL is recommended to prevent first variceal bleeding. (A1) A combination
of NSBBs and EVL can also be considered. (B2)
Diagnosis and management of acute esophageal variceal bleeding
Diagnosis of acute esophageal variceal bleeding
In patients with upper gastrointestinal bleeding, variceal bleeding caused by portal
hypertension can be suspected if the patients show jaundice, ascites, HE, splenomegaly,
collateral circulation of the abdominal vessels, lower extremity edema, or spider
angiomas. A definite diagnosis can be established by endoscopic examination. If blood
clots or white nipples appear on the surface of the varices, or if blood is found
in the stomach without a potential bleeding focus other than EVs, acute EV bleeding
can be diagnosed [45].
General management of acute esophageal variceal bleeding
Acute EV bleeding is a medical emergency requiring intensive care. It is essential
to protect the circulatory and respiratory status of the patient regardless of the
cause of bleeding. Volume resuscitation via adequate fluid therapy and a packed red
blood cell (PRBC) transfusion should be initiated to restore and maintain hemodynamic
stability. A recent RCT showed that bleeding-related mortality (5% vs. 9%, P=0.02)
and the incidence of serious adverse events (12% vs. 18%, P=0.01) were significantly
decreased in the “restrictive” PRBC transfusion group (initiating PRBC transfusion
at a hemoglobin threshold of 7 g/dL and maintaining it at 7–9 g/dL) compared with
the “liberal” PRBC transfusion group [83]. Improved survival in the restrictive transfusion
group might be associated with lower rates of hemostasis failure and serious adverse
events. In patients with acute EV bleeding, adequate fluid therapy/PRBC transfusion
should be performed while considering age, cardiovascular disease, presence or absence
of ongoing bleeding, and hemodynamic status. Excessive fluid therapy/PRBC transfusion
may increase the portal pressure and aggravate bleeding from the varices, so that
should be taken into account [84]. Regarding correction of coagulopathy, clinical
studies of recombinant factor VIIa have not shown a clear benefit, and therefore the
routine use of fresh frozen plasma or recombinant factor VIIa is not recommended [85,86].
Although the efficacy of platelet transfusion in patients with acute EV bleeding has
not been proven because of a lack of clinical studies, it can be considered in patients
with severe thrombocytopenia.
Pharmacological treatment of acute esophageal variceal bleeding
Cirrhotic patients presenting with acute gastrointestinal bleeding have a high risk
of developing bacterial infections, therefore initiation of prophylactic antibiotic
treatment at the time of admission is necessary. Meta-analyses of RCTs have shown
that the use of antibiotic prophylaxis reduces the risk of infections, recurrent bleeding,
and bleeding-related death [87,88]. A recent meta-analysis demonstrated that prophylactic
antibiotic treatment was associated with a decrease in bleeding-related mortality
(RR, 0.79; 95% CI, 0.63–0.98), mortality from bacterial infections (RR, 0.43; 95%
CI, 0.19–0.97), development of bacterial infections (RR, 0.35; 95% CI, 0.26–0.47),
and rebleeding (RR, 0.53; 95% CI, 0.38–0.74) [88]. However, another recent retrospective
study questioned the usefulness of the routine antibiotic prophylaxis in cirrhotic
patients experiencing acute variceal bleeding because of a very low incidence of bacterial
infections (2%) and mortality (0.4%) in Child-Pugh class A patients with acute variceal
bleeding, even in the absence of prophylactic antibiotic treatment [89]. No prospective
study has evaluated the usefulness of antibiotic prophylaxis, and therefore the routine
use of prophylactic antibiotics is recommended for all cirrhotic patients presenting
with variceal bleeding, regardless of their Child-Pugh class. In a previous RCT comparing
intravenous ceftriaxone (1 g every 24 hours) and oral norfloxacin (400 mg every 12
hours) for the prophylaxis of bacterial infection in cirrhotic patients with gastrointestinal
bleeding, the incidence of proven or possible infections (11% vs. 33%, P=0.003), proven
infections (11% vs. 26%, P=0.03), and spontaneous bacterial peritonitis or bacteremia
(2% vs. 12%, P=0.03) was significantly lower in the ceftriaxone group [90]. However,
controversy remains about whether those results are applicable to general cirrhotic
patients because that was study conducted in Spain among patients with advanced cirrhosis,
and most of the Gram-negative bacilli detected in the patients receiving oral norfloxacin
were norfloxacin-resistant strains. Therefore, it is necessary to select appropriate
antibiotics based on local antimicrobial susceptibility patterns. Generally, short-term
(maximum 7 days) antibiotic prophylaxis with intravenous ceftriaxone (1 g every 24
hours) is recommended in patients with acute variceal bleeding.
Vasoactive agents, such as vasopressin, terlipressin, somatostatin, and octreotide,
are effective in supporting hemostasis in patients with acute variceal bleeding by
decreasing portal pressure. In a meta-analysis, the use of vasoactive agents in patients
with acute variceal bleeding was significantly associated with a reduction in 7-day
mortality (RR, 0.74; 95% CI, 0.57–0.95) and an increase in the hemostasis rate (RR,
1.21; 95% CI, 1.13–1.30) [91]. In patients with suspected variceal bleeding, vasoactive
agents should be initiated as soon as possible, together with prophylactic antibiotics,
before the diagnostic endoscopy. Vasopressin reduces portal pressure by inducing systemic
and splanchnic vasoconstriction, but it is not now recommended for patients with acute
variceal bleeding because of the significant side effects, such as an increase in
peripheral vascular resistance and reduction in cardiac output and coronary blood
flow. Although terlipressin, a synthetic analogue of vasopressin, is the only drug
proven to reduce bleeding-related mortality (RR, 0.66; 95% CI, 0.49–0.88) [92], its
side effects, such as hyponatremia and myocardial ischemia due to coronary artery
vasoconstriction, should be considered [93,94]. A recent meta-analysis [91] and a
Korean multicenter RCT [11] comparing three vasoactive agents (terlipressin, somatostatin,
and octreotide) found no significant differences among them regarding the hemostasis
rate and survival time. In patients with acute variceal bleeding, it is recommended
that one of the vasoactive agents should be started as soon as possible (Table 2)
and continued for 3–5 days [26,47].
Endoscopic treatment of acute esophageal variceal bleeding
If acute variceal bleeding is suspected, endoscopy should be performed as soon as
possible to confirm the hemorrhagic focus and hemostasis. Endoscopic hemostasis should
be done when acute EV hemorrhage is confirmed by endoscopy. EVL is the endoscopic
treatment of choice for patients with acute bleeding from EVs. Endoscopic injection
sclerotherapy (EIS) is no longer recommended as standard treatment for acute EV bleeding
because of its higher incidence of treatment failure, bleeding-related mortality,
and adverse events compared with EVL [95-99]. In a meta-analysis comparing EVL and
EIS in patients with acute EV bleeding, bleeding-related mortality did not differ
significantly (RR, 0.95; 95% CI, 0.77–1.17), but the risk of rebleeding was reduced
(RR, 0.68; 95% CI, 0.57–0.81) and the rate of variceal eradication was increased (RR,
1.06; 95% CI, 1.01–1.12) in patients undergoing EVL compared with EIS [100]. Most
practice guidelines recommend endoscopy within 12 hours after presentation with suspected
variceal bleeding, but that recommendation lacks evidence. A previous Taiwanese retrospective
study reported that delayed endoscopy (>15 hours after admission) was an independent
risk factor of inhospital mortality (odds ratio [OR], 3.67; 95% CI, 1.27–10.39) [101].
In addition, a prospective observational study of 101 patients with acute EV bleeding
showed that the 6-week rebleeding rate (18.9% vs. 38.9%, P=0.028) and mortality (27%
vs. 52.8%, P=0.031) were significantly lowered in patients undergoing early endoscopy
(≤12 hours) compared with those undergoing delayed endoscopy (>12 hours) [102]. However,
because those studies were performed without randomization, several confounders that
can delay the endoscopy, such as hemodynamic instability, might have influenced the
results. Therefore, until the results of large RCTs are reported, endoscopy should
be performed as soon as possible in patients with suspected acute EV bleeding. However,
the specific timing should be determined by the hemodynamic status of individual patients
and the experience and medical resources of the institution.
Once endoscopy and EVL have been performed, early placement of a transjugular intrahepatic
portosystemic shunt (TIPS) can be considered in carefully selected patients at high
risk for rebleeding. Early TIPS placement reduced the rates of treatment failure and
bleeding-related mortality in an RCT [103] of patients with a HVPG >20 mmHg and in
an RCT [104] of patients with Child-Pugh class C cirrhosis (score of 10–13) or Child-Pugh
class B cirrhosis with active bleeding on endoscopy despite intravenous administration
of a vasoactive agent. However, because these two trials excluded patients with Child-Pugh
class A cirrhosis, Child-Pugh class B cirrhosis without active bleeding during endoscopy,
ChildPugh class C with a score of 14–15, patients >75 years, HCC beyond the Milan
criteria, or a creatinine level greater than 3 mg/dL, it should be considered that
those study results apply to only a very small portion of patients with acute variceal
bleeding. Notably, a recent prospective observational study showed that the 1-year
rebleeding risk was significantly decreased (3% vs. 49%, P<0.001), but 1-year survival
did not differ between patients with and without a TIPS (66.8±9.4% vs. 74.2±7.8%,
P=0.78) [105]. Further studies are needed to evaluate the beneficial effect of early
TIPS placement.
Recently, the efficacy of applying hemostatic powder via endoscopy within 2 hours
of admission was evaluated in 86 randomized patients with acute variceal bleeding
[106]. Cirrhotic patients with acute variceal bleeding received standard medical treatment
and were randomized to receive either immediate endoscopy with hemostatic powder application
within 2 hours of admission followed by early elective endoscopy the next day (that
is, within 12–24 hours of admission) for definitive treatment (EVL for EV bleeding
or endoscopic variceal obturation [EVO] for gastric variceal bleeding; study group)
or early elective endoscopy only (control group). Improved rates of hemostasis and
survival time in the study group suggested the therapeutic potential of endoscopic
application of hemostatic powder, an easy procedure requiring minimal expertise.
Rescue treatment for patients with hemostasis failure
Failure to control acute EV bleeding is defined as death or the need to change therapy
(defined by one of the following criteria) within 5 days of an acute bleeding episode
[107].
- Fresh hematemesis of ≥100 mL of fresh blood ≥2 hours after the start of a specific
pharmacological treatment or therapeutic endoscopy
- Development of hypovolemic shock
- 3 g drop in hemoglobin (9% drop in hematocrit) within 24 hours without transfusion
TIPS placement is considered the best rescue treatment for patients with inadequate
bleeding control despite combined pharmacological and endoscopic therapy [108]. A
prospective observational study to evaluate the efficacy of TIPS in 58 patients who
failed to achieve hemostasis after EIS and pharmacological treatment reported that
the TIPS achieved control of the bleeding in 52 patients (90%), and 1-year and 3-year
survival rates were 51.7% and 40.2%, respectively [108]. Balloon tamponade is still
used as a bridge therapy and provides hemostasis in 80–90% of patients, but the rebleeding
rate after deflation is as high as approximately 50% [109,110]. Moreover, because
it is associated with a high rate of serious complications, such as esophageal ulceration,
esophageal rupture, and aspiration pneumonia, balloon tamponade should not exceed
24 hours [111]. In a small RCT, a self-expandable, esophageal covered metal stent
was tested as an alternative to balloon tamponade in patients in whom pharmacological
and endoscopic treatment failed to control bleeding [112]. Although survival in the
esophageal stent group was not improved compared with the balloon tamponade group,
bleeding control was higher (85% vs. 47%, P=0.037), and serious adverse events were
lower (15% vs. 47%, P=0.077) in the esophageal stent group [112]. This stent can be
placed endoscopically without radiological guidance, and it can stay in place for
up to 2 weeks. However, because only 28 patients were included in that study, further
study is warranted.
[Recommendations]
1. Endoscopy should be performed in patients with suspected esophageal variceal bleeding.
(A1)
2. Endoscopic treatment should be performed in patients with acute esophageal variceal
bleeding. (A1)
3. In patients with acute esophageal variceal bleeding, restrictive PRBC transfusion
is recommended with the goal of maintaining a hemoglobin level of 7–9 g/dL. (A1)
4. Short-term antibiotic prophylaxis should be instituted in patients with acute esophageal
variceal bleeding. (A1)
5. If esophageal variceal bleeding is suspected, vasoactive agents should be initiated
as soon as possible after admission. (A1)
6. Early TIPS placement can be considered in patients at high risk of rebleeding.
(B2)
7. A TIPS is a possible rescue treatment for patients in whom bleeding control fails
despite combined pharmacological and endoscopic therapy. (A2)
8. Balloon tamponade can be considered as a bridge therapy for patients who fail to
achieve hemostasis after endoscopic treatment. (B2)
Prevention of esophageal variceal rebleeding
Definition of esophageal variceal rebleeding
EV rebleeding is defined as recurrent bleeding after an absence of bleeding for at
least 5 days following recovery from acute EV bleeding [107]. An average of 60% of
patients with acute EV bleeding experience rebleeding within 1–2 years, and the mortality
rate from rebleeding is 33%. Therefore, appropriate treatment to prevent rebleeding
is necessary [15,48].
Diagnosis of esophageal variceal rebleeding
The diagnosis of EV rebleeding is the same as the diagnosis of acute EV bleeding.
Clinically significant rebleeding can be suspected in a patient who has recurrent
melena or hematemesis with 1) hospitalization or the need for a transfusion, 2) a
decrease in hemoglobin of more than 3 g /dL, or 3) death within 6 weeks [107].
Prevention of esophageal variceal rebleeding
NSBBs and EVL are the most common methods used to prevent EV rebleeding. NSBBs, which
reduce portal pressure, have been reported to be more effective than placebo at preventing
rebleeding in several RCTs [113-115]. The combination of an NSBBs plus ISMN could
improve portal pressure reduction [116], but it could also increase the incidence
of side effects such as headache and dizziness [117]. EVL is the endoscopic treatment
of choice for the prevention of EV rebleeding. EVL should be repeated every 2–8 weeks
until variceal eradication is achieved. Periodic endoscopic follow-up is needed to
detect the recurrence of varices even after achievement of variceal eradication. Several
systematic reviews and meta-analyses comparing EVL alone to NSBBs alone demonstrated
no difference in the rebleeding rate [51,118,119], but the overall mortality rate
during follow-up was significant higher with EVL alone (RR, 1.25; 95% CI, 1.01–1.55)
[51] or not different [119]. In a long-term follow-up study, the rebleeding rate was
higher (30% vs. 64%, P=0.001) but the survival time was longer (30% vs. 49%, P=0.013)
in patients treated with the combination of an NSBBs plus ISMN [120].
Several RCTs and meta-analyses comparing the combination of EVL plus NSBBs to EVL
alone or NSBBs alone showed that the combination therapy had lower overall rebleeding
and variceal rebleeding [121-124]. Therefore, the combination of EVL plus an NSBBs
has been suggested as the primary treatment for preventing EV rebleeding. A recent
meta-analysis demonstrated that the rebleeding rate decreased (RR, 0.44; 95% CI, 0.28–0.69)
and the mortality rate during follow-up tended to decrease with the combination of
EVL plus a NSBBs (RR, 0.58; 95% CI, 0.33–1.03) compared with EVL alone. However, although
the overall rebleeding rate tended to decrease (RR, 0.76; 95% CI, 0.58–1.00), the
mortality rate during follow-up did not differ between the combination of EVL plus
NSBBs and NSBBs alone [125]. These results suggest the importance of NSBBs in preventing
EV bleeding.
RCTs comparing carvedilol to EVL (36.4% vs. 35.5%, P=0.857) and carvedilol to the
combination of nadolol plus ISMN (51% vs. 43%, P=0.46) did not show any significant
difference in rebleeding rate, and the side effects of carvedilol were less than those
with the combination of nadolol plus ISMN (1.6% vs. 28.3%, P<0.0001) [126,127]. Therefore,
the use of carvedilol to prevent EV rebleeding can be considered, but no studies have
compared the combination of EVL plus carvedilol with the combination of EVL plus an
NSBBs, which is currently considered to be the primary treatment to prevent rebleeding.
Further studies using carvedilol to prevent EV rebleeding are required.
In a meta-analysis of studies about preventing variceal rebleeding by using NSBBs
to reduce portal pressure, the risk of variceal rebleeding was significantly reduced
(OR, 0.17; 95% CI, 0.09–0.33; P=0.0001) when the HVPG was decreased to the target
level (reduction in HVPG of ≥20% or to ≤12 mmHg) compared with the non-responding
group [128]. A recent RCT comparing HVPGbased medical therapy with TIPS placement
to reduce variceal rebleeding showed lower incidence of rebleeding within 2 years
(26% vs. 7%, P=0.002) in the TIPS group, but there was no significant difference in
mortality during follow-up between the two groups, and the incidence of HE was lower
(8% vs. 18%, P=0.05) in the HVPG-based medical therapy group [129]. Considering that
a TIPS is a limited treatment method, HVPG-based medical therapy is a useful way to
prevent rebleeding if HVPG measurement is possible. However, because HVPG measurement
is invasive, it is not widely practiced in many hospitals.
An RCT comparing TIPS placement with a combination of EVL plus an NSBBs to prevent
variceal rebleeding found a lower variceal rebleeding rate in the TIPS group (0% vs.
29%, P=0.001), but the incidence of HE within 1 year in that group was higher (35%
vs. 14%, P=0.035). There was no difference in the follow-up mortality rate (32% vs.
26%, P=0.418) between the two groups [130]. Therefore, the use of TIPS is not recommended
as a primary treatment for the prevention of variceal rebleeding, and it should instead
be considered a rescue therapy for patients with primary treatment failure [131].
In addition, liver transplantation is considered a rescue therapy for patients with
recurrent variceal rebleeding because it exhibits good long-term results [132,133].
[Recommendations]
1. In patients with acute esophageal variceal bleeding, treatment to prevent variceal
rebleeding is recommended. (A1)
2. The combination of endoscopic variceal ligation (EVL) plus NSBBs is recommended
as the primary treatment for esophageal variceal bleeding. (A1) If the combination
treatment is difficult to perform, use of a NSBBs or EVL alone is recommended. (A1)
3. If primary treatment for esophageal variceal rebleeding fails, TIPS placement should
be considered as a rescue therapy. (B1)
4. Liver transplantation might be considered in patients with recurrent variceal rebleeding.
(B1)
Definition of gastric varices and prevention of primary bleeding
Definition and classification of gastric varices
Gastric varices are enlarged submucosal veins of the stomach that cause critical upper
gastrointestinal bleeding. GVs occur in approximately 20% of patients with portal
hypertension, and the bleeding rate in 2 years is known to be 25% [134]. The incidence
of gastric varices is lower than that of EVs, but their rebleeding rate and mortality
rate are higher because they cause severe bleeding [134-136].
Gastric varices are classified as gastroesophageal varices (GOV) or isolated gastric
varices (IGV) depending on their location and relation to any EVs (Fig. 1). GOVs are
classified by whether they extend along the lesser curvature (GOV1) or the gastric
fundus (GOV2). IGV are classified as varices located in the fundus (IGV1) and those
in any other region, i.e., stomach or duodenum (IGV2) [134]. The incidence of GOV1s
is about 74%.
Prevention of primary bleeding of gastric varices
The risk factors for gastric variceal bleeding are location (IGV1>GOV2>GOV1), variceal
size, redness, and severe liver dysfunction [26,47,93,137-139].
To prevent bleeding from GOV1s, follow the guidelines for the prevention of EV bleeding.
In a Korean study of 85 patients with GOV1s, the GOV1s also disappeared when EVs were
eliminated by EVL (64.7%) [140]. For GOV2s and IGV1s, EVO, balloon-occluded retrograde
transvenous obliteration (BRTO), and vascular plug-assisted retrograde transvenous
obliteration (PARTO) can be considered to prevent bleeding [141,142]. NSBBs are non-invasive
and can be used because they can reduce other side effects in patients with cirrhosis.
One randomized study reported the prevention of first gastric variceal bleeding. It
enrolled 89 patients with GOV2s or IGV1s larger than 10 mm [141]. The effects of EVO
(cyanoacrylate), an NSBB, and simple observation were compared. For the prevention
of gastric variceal bleeding, EVO (10%) was superior to an NSBB (38%) and simple observation
(53%) [141]. The survival rate of the EVO group (93%) was higher than that of the
simple observation group (73%), but it did not differ from that of the NSBB group
(83%). In a meta-analysis of patients with a high risk of gastric variceal bleeding,
BRTO was effective in preventing gastric variceal bleeding (clinical success rate,
97.3%) [142]. In a recent study of 73 patients, PARTO was found to be a safe procedure
without serious side effects that effectively prevented gastric variceal bleeding
(Fig. 2) [143,144].
[Recommendations]
1. Primary prevention of bleeding for GOV1s follows the recommendations for EVs. (B1)
2. The group at high risk for bleeding (redness or severe liver dysfunction) from
GOV2s or IGV1s can be treated with BRTO, PARTO, or EVO. (B2)
Management of bleeding from gastric varices
Bleeding from gastric varices is less common than from EVs; however, the risks of
rebleeding or varix-related death are much higher in patients bleeding from gastric
varices. The gastric varices that bleed are generally large and have high blood flow
in the channel, which makes massive bleeding common in patients with large gastric
varices [134,145,146]. Gastric varices exhibit unique characteristics and have a greater
variety of sizes, forms, locations, and collateral vessels than EVs. An individualized
approach might be needed because few well-controlled clinical trials have tested treatments
for gastric variceal bleeding. Until sufficient evidence accumulates, clinicians should
seek the best option for each patient based on the patient’s general condition and
bleeding patterns and the clinician’s medical resources and expertise [145].
Management of bleeding from gastric varices
Endoscopic therapy
Urgent endoscopic examination, within 12 to 24 hours, is necessary when a patient
is suspected to have active bleeding from gastric varices. Endoscopic examination
can visualize the bleeding sites and directly enable proper hemostatic treatments
[47,147].
EVO
EVO achieves hemostasis and induces variceal eradication by an intravariceal injection
of tissue adhesive agents (cyanoacrylates). Active or recent bleeding from fundic
varices (GOV2s, IGV1s) or GOV1s can be managed with EVO. Special care is needed to
prevent complications from the adhesive agents, such as ocular injury, damage to endoscopic
devices, or the impaction of an injection needle into a varix [148]. Medical personnel
are advised to wear goggles during the procedure. The working channel of a scope can
be occluded by adhesive agent that spills during the procedure, so it can be helpful
to flush the channel with olive oil in advance. To inject the sticky mixture quickly,
a large needle is generally used (21 G or 22 G). The injection site is determined
based on the direction of blood flow inside the varix. Because the intravariceal pressure
is usually concentrated in the most protruding part of the varix, avoid that site
if possible. The injection needle should be long enough to pass through the thick
gastric wall (5 mm or longer). 2-N-butyl cyanoacrylate, which is the most commonly
used agent in Korea, is used as a 1:1 mixture with lipiodol to delay the polymerization
reaction. About 1 mL of mixture is used in each session, and the injection can be
repeated until hemostasis is achieved. The initial volume and ratio of the mixture
can be adjusted to accommodate the variceal size, intravariceal blood flow, and bleeding
pattern (active or stabilized). If the bleeding is severe or the variceal size is
large, the volume of the mixture can be increased to 2 mL at a time. As soon as the
injection is finished, 1 mL of distilled water or saline should be pushed into the
catheter to ensure that the mixture remaining in the catheter is injected into the
varix. Then, the needle should be retracted quickly to prevent intravariceal impaction
of the needle. The success rate of EVO for hemostasis was 91–97%, and the rebleeding
rate was 17–49% in patients with active gastric variceal bleeding [149-153]. The common
complications following EVO are systemic embolism, infection, fever, gastric perforation,
gastric ulcer, and peritonitis [154].
EVL
As with EVs, EVL is frequently performed for GOV1 bleeding. EVL for gastric varices
showed an initial hemostasis rate of 80–90% and a rebleeding rate of 14–56% in patients
with GOV1s [140,155-158]. However, it should be noted that the depth and size of gastric
varices differ from those of EVs. Ligation might not be adequate due to the thick
gastric mucosa. Gastric ulcers, where the bands fall off, will expose submucosal varices
directly to gastric acid and food materials. This situation could increase the risk
of massive bleeding from the ulcers [154,155,158,159]. In patients with fundal variceal
bleeding, the effect or safety of EVL has not been fully explored. In a small randomized
trial, EVL showed a significantly higher rebleeding rate than EVO in patients with
IGV1 bleeding (83.3% vs. 7.7%, P=0.003) [155].
Radiologic intervention
Radiologic intervention is one useful hemostatic therapy for the management of bleeding
from gastric varices. Sufficient consultation with interventional radiologists is
needed in advance. Imaging tests, such as computed tomography (CT), should be performed
before the procedure to confirm that the collateral veins are accessible and that
no contraindications to the procedure are present.
TIPS
TIPS placement is a procedure that robustly decompresses portal hypertension by making
a bypass between the hepatic vein and the portal vein. In small non-randomized trials,
both TIPS and EVO achieved a hemostasis rate of more than 90%. Complications, such
as HE and stent occlusion, and medical costs were higher with the TIPS than with EVO
[160,161]. However, TIPS placement is a useful rescue therapy when initial hemostasis
fails [162-164]. The success rate of TIPS in controlling bleeding as a rescue therapy
is 90–100%, with a rebleeding rate of 16–40% [162-166]. Moreover, since non-covered
stents have been replaced by covered stents, the occlusion and stenosis rates have
decreased to 8% [167,168]. HE can be prevented by decreasing the stent diameter. In
a randomized study, the incidence rates of HE within 2 years were 43% and 27% in patients
with a conventional stent (10 mm) and those with a smaller one (8 mm), respectively
(P=0.03) [168]. TIPS is contraindicated in patients with heart failure or severe pulmonary
hypertension because it can abruptly increase preload to the heart. It is difficult
to perform the procedure in patients with main portal vein thrombosis. When a cyst,
abscess, or mass is blocking the accessible tract in the liver or the intrahepatic
bile ducts are markedly dilated, it is difficult to perform TIPS [169].
RTO
RTO obliterates gastric varices by infusing a sclerosant or embolic agent in a retrograde
manner through a gastrorenal shunt. An accessible shunt should be confirmed by CT
prior to the procedure. After occluding the shunt with a balloon catheter, a sclerosant,
such as ethanolamine oleate or sodium tetradecyl sulfate, is infused into the gastric
varices [170,171]. In a recent, large, retrospective study, the technical success
rate of BRTO was 95% [172]. Another multicenter study, in which 23% of patients had
GOV1s, had a technical success rate of 97% [173]. However, the EVs recurred or became
aggravated in 20–41% of patients after the procedure [172,173]. A recent meta-analysis
also showed favorable results. The technical success and major complication rates
of BRTO were 96.4% and 2.6%, respectively. The clinical success rate, defined as no
recurrence of gastric varices or complete obliteration of varices on subsequent imaging,
was 97.3% [142].
If a shunt is too large for balloon catheter occlusion, BRTO is not possible. Moreover,
BRTO requires that patients retain the balloon catheter for several hours, until the
sclerosing agent has hardened in the varices. In rare cases, the balloon can rupture
during the procedure, and a systemic embolism of the sclerosing agent can occur. Therefore,
a novel intervention, PARTO, was recently developed. PARTO uses a vascular plug with
or without coils instead of a balloon and uses a gelatin sponge as the embolic agent
[143]. A multicenter prospective study showed that complete thrombosis of gastric
varices and shunts was achieved in 98.6% of patients. No recurrent variceal bleeding
or development of HE occurred during follow-up. Moreover, 40% of patients showed improvement
in their Child-Pugh scores [144]. Thus, PARTO is a noteworthy treatment that can replace
BRTO in patients with gastric varices and a gastrorenal shunt. However, more data
on the long-term efficacy and safety of PARTO are needed.
Treatment of gastric variceal bleeding
General management of gastric variceal bleeding
In patients with cirrhosis and acute upper gastrointestinal bleeding, a restrictive
blood transfusion strategy (with a target range for the post-transfusion hemoglobin
level of 7 to 9 g/dL) and antibiotic prophylaxis improved survival [83,174]. Although
patients enrolled in the studies were small, the same transfusion strategy can be
recommended for those with gastric variceal bleeding. The beneficial effects of vasoactive
agents (terlipressin, octreotide, somatostatin) have not been fully proved in patients
with gastric variceal bleeding, either. However, considering their ability to decrease
portal hypertension, their use in patients with bleeding from gastric varices can
be recommended [91,158,175,176].
Treatment of GOV1 bleeding
GOV1s, which are an extended type of EV, develop along the lesser curvature and receive
blood from the left gastric vein. When EVs are eradicated by endoscopic treatments,
the gastric varices also concomitantly disappear in 60–65% of patients [134,140].
Because of their close relationship in pathophysiology, the management of bleeding
from cardiac varices (GOV1s) is similar to that for EV bleeding [177]. However, it
should be noted that sufficient ligation can be difficult for gastric varices because
of their large size and deeper location. Furthermore, subsequent post-ligation ulcers
might be exposed to gastric acid or food material [154,155,158,159]. According to
small clinical trials and observational studies, EVO produces more favorable outcomes
than EVL. The initial hemostasis rates with EVO and EVL in patients with GOV1 bleeding
were 85–100% and 80–90%, respectively. The rebleeding rates following EVO and EVL
were 3–26% and 14–56%, respectively [140,155-158]. However, most of those trials were
small; the evidence needed to recommend one of these treatments over the other remains
insufficient [140,155,157,158,178]. Therefore, clinicians may choose either EVO or
EVL based on their expertise, available medical resources, and the variceal condition
(size or extent).
Treatment of GOV2 or IGV1 bleeding
GOV2s are a type of gastric varix that extends from EVs toward the fundus. IGV1s are
varices localized in the fundus in the absence of EVs [134]. Both GOV2s and IGV1s
are usually called gastric fundic varices. Unlike EVs, fundic varices are supplied
with blood from the posterior gastric vein or short gastric vein [179,180]. Bleeding
from the fundus usually occurs in a stage of large varix. Management of fundic variceal
bleeding can be difficult because massive or recurrent bleeding is frequently accompanied.
Moreover, collateral shunts or blood circulation around the fundic varices are very
diverse. Therefore, it is difficult to apply simple or uniform treatments for fundic
variceal bleeding [181]. Urgent endoscopic examination is always needed in patients
with suspicious fundic variceal bleeding in order to direct visualization of bleeding
sites and to apply immediate treatments. EVO is one of the most commonly performed
in patients with bleeding from fundic varices [182] EVO achieved initial hemostasis
more often than EVL (OR, 4.44; 95% CI, 1.14–17.3). In particular, the rebleeding rate
following EVO was significantly lower than that following EVL in patients with IGV1s
(OR, 0.06; 95% CI, 0.01–0.58) [183]. TIPS placement and EVO are both effective treatments
to control bleeding, with a hemostasis rate of more than 90%. Because of complications
such as HE, stent occlusion, and higher cost, TIPS placement over EVO is not recommended
as a first-line treatment [160,161]. However, TIPS placement is an effective rescue
therapy when endoscopic therapy fails. The hemostasis rate of TIPS in a rescue setting
is 90–100% [162-166]. BRTO also achieved a high hemostasis rate (more than 90%) [184-186].
However, BRTO showed a significantly lower rebleeding risk (OR, 0.27; 95% CI, 0.09–0.81)
and a lower risk of HE (OR, 0.05; 95% CI, 0.02–0.13) than TIPS [186]. Improvement
in liver function was also demonstrated following BRTO [187]. However, all those results
are based on mostly small retrospective studies.
In a small prospective study, BRTO and EVO had similar hemostasis and technical success
rates. However, the rebleeding rate was significantly lower in the BRTO group than
the EVO group (15.4% vs. 71.4%, P<0.01) [188]. These results should be interpreted
carefully, however, because BRTO was performed only in patients without active bleeding;
all the patients with active bleeding were treated with EVO.
In summary, current data suggest that EVO, TIPS, BRTO, or (theoretically) PARTO can
be used as the initial treatment for patients bleeding from fundic varices. Because
of a lack of evidence, treatments should be chosen based on individual situations
in consideration of patients’ safety and the applicability of each therapy in the
relevant medical facility.
Use of PPIs
Currently, PPIs are used in many patients to prevent ulcer bleeding following endoscopic
treatments. However, their effectiveness and duration of treatment have not been fully
explored. Long-term use of PPI can increase risk of infection and subsequently cause
spontaneous bacterial peritonitis and HE [79]. However, a recent retrospective study
showed that PPI use decreased the rebleeding risk following EVO (OR, 0.554; 95% CI,
0.352–0.873) [189].
Rescue therapy in case of endoscopic failure
A TIPS can be urgently placed when endoscopic treatments fail. The hemostasis rate
with rescue TIPS was 90–96% in patients with gastric varices, which is comparable
to that with EV bleeding [162,163]. In a few small studies, BRTO also showed comparable
outcomes in patients who failed to achieve initial hemostasis. BRTO can be considered
as a rescue therapy when a patient was hemodynamically stabilized and has an accompanying
gastrorenal shunt [184,186]. As a bridging therapy, a balloon tamponade can be applied
to control massive bleeding until rescue therapy is ready [109].
[Recommendations]
1. In p atient s with gas tric variceal b le e ding, gener al management, such as
prophylactic antibiotics, restrictive transfusion, and vasoactive agents, can be provided
as they are for esophageal variceal bleeding. (B1)
2. Gastric varices extending from EVs along the lesser curvature (GOV1s) can be treated
with either EVO or EVL, depending on the size and location of the bleeding varix.
(B1)
3. In patients with bleeding from fundic varices (GOV2s, IGV1s), EVO should be considered
first. (A1) Retrograde transvenous obliteration (BRTO or PARTO) or TIPS can be used
depending on the bleeding status (active or stabilized) and the presence of an accessible
shunt. (B1)
4. A PPI can be used following endoscopic treatments to prevent post-procedure ulcer
bleeding. (B2)
5. Retrograde transvenous obliteration (BRTO or PARTO) or TIPS should be considered
as a rescue therapy when endoscopic treatments fail. (B1)
6. Until a rescue therapy is ready, a balloon tamponade can be applied as a bridging
therapy. (B2)
Prevention of rebleeding
GOV1s can be managed in the same way as EVs to prevent rebleeding. The eradication
of concurrent EVs with EVL and an NSBB can be used if the EVs are medium to large
in diameter. Gastric varices subsequently disappeared in 65% of patients when EVs
were controlled [140]. The rebleeding rate from GOV1s following eradication of EVs
was 16–42% [155,156]. Esophageal EVL can be performed simultaneously with or after
treatments for gastric varices. In terms of gastric varices, EVO showed a significantly
lower rebleeding rate than EVL in patients bleeding from GOV1s (OR, 0.39; 95% CI,
0.16–0.94) [155,158,183]. However, those studies included only a small number of patients.
In a retrospective Korean study, EVO showed beneficial outcomes, with lower 1-year
rebleeding rate (3.6% vs. 30.8%, P=0.004) and bleeding-related mortality rate (5%
vs. 22%, P=0.05) than EVL [140]. In a different small study, TIPS placement showed
a significantly lower rebleeding rate than EVO (21% vs. 65%, P<0.02) [190]. However,
it is difficult to draw conclusions from that study alone because its rebleeding rate
following EVO was relatively higher than previous reports. If an accessible gastrorenal
shunt is identified, BRTO or PARTO might be considered. Unfortunately, evidence to
support those interventions in patients with GOV1 bleeding is very limited [173,191].
In patients bleeding from fundic varices (GOV2s or IGV1s), the only predictor for
rebleeding following EVO was variceal size (F3). The use of NSBBs failed to decrease
the rebleeding rate [192]. In an RCT, eradication of gastric varices with repeated
EVO lowered the rebleeding rate significantly compared with NSBBs (10% vs. 44%, P=0.004)
[193]. There were no differences in rebleeding (54% vs. 47%, P=0.609) or bleeding-related
mortality (42% vs. 47%, P=0.766) between EVO alone and EVO plus an NSBB, respectively
[194]. Therefore, use of an NSBB is not recommended to prevent recurrent bleeding
from fundic varices. However, NSBBs should be considered if patients have significant
portal hypertension or other proven indications, such as large EVs [47]. Clinical
trials comparing the rebleeding rates after repeated EVO and TIPS or BRTO are scarce.
In a small randomized study of patients with GOV2 bleeding, there was no significant
difference in the rebleeding rate between EVO repeated every 4 weeks and TIPS placement
(16% vs. 0%, P>0.05) [190]. However, TIPS placement was associated with a higher incidence
of complications than EVO [161]. In a meta-analysis, BRTO (7.4%) showed a much lower
rebleeding rate than TIPS (22.8%) (OR, 0.27; 95% CI, 0.09–0.81) [186]. For GOV2s,
treatment of the accompanying EVs can be performed with or after the treatment of
fundic varices, according to the guidelines for treating EVs (Fig. 3).
[Recommendations]
1. In patients with remnant or recurrent GOV1s following initial treatments, repeated
EVO or EVL can be performed to prevent rebleeding. (B2)
2. In patients with remnant or recurrent fundic varices (GOV2s, IGV1s), EVO or RTO
(BRTO or PARTO) can be performed. (B2) If there is no accessible shunt or if complications
related to severe portal hypertension (recurrent bleeding from EVs, refractory ascites,
or hydrothorax) are not controlled, a TIPS can be placed. (B2)
Other variceal bleeding
In cirrhosis, variceal bleeding at sites other than the stomach and esophagus is very
rare, and there are no established treatment guidelines. The most common locations
are the rectum, duodenum, and postoperative stomach. A multi-disciplinary approach
involving an endoscopist, interventional radiologists, and surgeons should be used
to account for the vascular supply. EVO, BRTO, PARTO, TIPS, the coil inserting method,
and the like can all be used [195].
Portal hypertensive gastropathy
Definition and diagnosis
Although the incidence of portal hypertensive gastropathy bleeding in cirrhosis is
not high, some patients experience poor quality of life due to chronic bleeding and
the associated iron-deficiency anemia and repeated transfusions [196,197]. Portal
hypertensive gastropathy is diagnosed when gastric mucosal changes cause a snake-skin
appearance or mosaic pattern on endoscopy in patients with portal hypertension [198-200].
When gastric mucosal changes alone are found, it is diagnosed as a mild form. When
red or dark brown viscous changes are found along with changes in the gastric mucosa,
it is considered to be severe (Fig. 4) [30]. Severe portal hypertensive gastropathy
causes more chronic bleeding than the mild form [201].
Portal hypertensive gastropathy is associated with portal hypertension and causes
gastric mucosal changes in the stomach and body, and 30% of patients with gastric
antral vascular ectasia (watermelon stomach) also have portal hypertension. It is
unclear whether portal hypertension is involved in the development of gastric antral
vascular ectasia. Gastric antral vascular ectasia causes dilated vessels with fibrin
thrombi and fibromuscular hyperplasia of the lamina propria [202].
Treatment of portal hypertensive gastropathy
In chronic bleeding caused by portal hypertensive gastropathy, the goal of treatment
is lowering the portal pressure with NSBBs, vasoconstrictors, or a TIPS [203,204].
In cases with active bleeding, endoscopic treatment with argon plasma coagulation
can be used. In addition, iron supplementation is recommended [205].
[Recommendations]
1. If chronic bleeding is caused by portal hypertensive gastropathy, nonselective
beta-blockers can be used. (B1)
HEPATIC ENCEPHALOPATHY
HE occurs in more than 10% of all cases of cirrhosis and is a critical complication
that seriously reduces the quality of life [206]. Because HE can cause serious losses
not just for individuals, but also socioeconomically, preventive therapy is of paramount
importance. However, because the pathophysiological factors in the development of
HE and biomarkers to predict the occurrence of HE have not been sufficiently identified,
there are no standardized criteria for diagnosing, classifying, or evaluating the
treatment response to HE. It is imperative that those criteria be established in Korea.
In particular, quality-of-life assessments and diet and exercise education for patients
with HE are clinically important and need to be actively developed.
Definition of HE
HE is a neuropsychiatric syndrome caused by hepatic dysfunction that manifests as
various neurologic and psychiatric abnormalities [207-209]. Clinically, it is classified
into overt and covert encephalopathy. Overt HE (OHE) is defined as the occurrence
of disorientation, flapping tremor, or asterixis (Table 3). Covert HE (CHE) includes
minimal encephalopathy in which cognitive impairment cannot be identified without
a cognitive function test and West-Haven criteria grade 1 HE, which means mild cognitive
or behavioral change without disorientation [210]. The prevalence of HE is reported
to be 10–14% of cirrhotic patients and 16–21% of patients with decompensated liver
cirrhosis [206,211]. In Korea, HE was found in 16–21% of hepatitis B virus–related
decompensated liver cirrhosis patients [212]. Moreover, 20% of cirrhotic patients
admitted to the emergency department were reported to have HE [213].
HE is classified according to the underlying liver disease, clinical course, precipitating
factors, and severity of neurologic symptoms [209]. By underlying liver disease, HE
is subdivided into three groups: from acute liver failure, from portosystemic bypass
or shunting, and from portal hypertension caused by chronic liver disease. HE caused
by portal hypertension is classified as episodic, recurrent (more than two times per
year), and persistent HE (no fully recovery from behavioral change). When classified
by the precipitating factors, HE is divided into precipitated and spontaneous types.
Precipitating factors include gastrointestinal bleeding, uremia, sedatives, diuretics,
protein overload, infection, constipation, dehydration, and electrolyte imbalance.
The severity of HE is classified using the West-Haven criteria (Table 3).
Diagnosis of HE
Clinical symptoms
HE presents with a wide range of clinical patterns, from minimal HE (MHE), in which
cognitive impairment cannot be identified without a cognitive function test, to OHE,
which is easily detected based solely on symptoms and does not require a cognitive
function test. As HE progresses, symptoms such as personality changes, indifference,
anxiety, and irritability appear and can reduce sleep quality and quality of life
[214]. In some patients, increased muscle tension, hyperreactivity, and the Babinski
reflex are present, and they are rarely accompanied by seizures [215,216]. The flapping
tremor, a phenomenon in which hand tremors are caused by incongruity in the tension
of various muscles resulting from hyperextension of the wrist as the fingers are spread
apart, is a common symptom in the early and middle phases of OHE.
Severity classification
The severity of HE is classified using the West-Haven criteria and the Glasgow Coma
Scale [207], with the former used as the basic diagnostic criteria. However, due to
their large number of subjective factors, the West-Haven criteria suffer from significant
interobserver deviation, which makes it difficult to diagnose the first stage (grade
1) of HE in a clinical setting. Therefore, MHE and stage 1 HE are classified as CHE
(Table 3) [217]. The International Society for Hepatic Encephalopathy and Nitrogen
Metabolism (ISHEN) defines the onset of disorientation or flapping tremor as the start
of OHE [218].
Differential diagnosis
HE requires differentiation from underlying brain diseases, such as cerebral hemorrhage
and edema, that can accompany cognitive dysfunction. It should also be differentiated
from substance abuse, alcoholism, hyponatremia, and psychiatric illnesses. In chronic
alcoholics in particular, it can be difficult to differentiate HE from other alcohol-related
neurological diseases. For example, Korsakoff syndrome, which is caused by a thiamine
deficiency induced by long-term drinking, is characterized by symptoms such as anterograde
amnesia and decreased word memory [219], and Wernicke’s encephalopathy is marked by
eye movement paralysis, gaze-induced nystagmus, and gait disturbances, in addition
to memory lapses [220]. Delirium caused by withdrawal from alcohol also needs to be
differentiated from HE. Delirium that results from alcohol withdrawal is characterized
by an increased heart rate, cold sweats, loud shouting, and a harsh and repetitive
tremor [221]. A differential diagnosis is required for acute hyponatremia, hypoglycemia,
and metabolic alkalosis because each can present with symptoms similar to those of
HE [222]. The differential diagnosis for hyponatremia requires particular caution
because its symptoms are very similar to those of HE, and hyponatremia itself can
lead to HE [223]. Subdural hematoma can also present with symptoms similar to those
of HE and should be carefully differentiated. Cases of subdural hematoma are commonly
accompanied by other neurological symptoms, such as hemiplegia. Encephalitis often
presents with symptoms such as headache, fever, vomiting, and stiff neck, but a differential
diagnosis is required because those symptoms are not always clear and can be accompanied
by sleepiness, drowsiness, and unconsciousness. In cases of dementia, the symptoms
appear relatively gradually in most cases, whereas alcohol-related dementia often
includes violent tendencies caused by frontal lobe damage, as well as the inability
to remember recent events [224].
Diagnostic tests
OHE can be diagnosed based solely on clinical symptoms, but other diseases that can
cause cognitive dysfunction should still be ruled out. Brain CT and brain magnetic
resonance imaging (MRI) are helpful for differentiating neuropsychological abnormalities
caused by underlying brain diseases, such as intracranial hemorrhage [225]. Because
the risk of cerebral hemorrhage is about five times higher in patients with liver
cirrhosis than in healthy people, brain CT or MRI should be performed if a brain lesion
is suspected [226]. Brain MRI, in particular, is helpful for diagnosing HE, in which
brain edema is associated with nonspecific symptoms such as headache and vomiting,
when acute liver failure is suspected [225]. On T1-weighted MRI, an increased signal
in the basal ganglia is commonly observed, but those changes lack the sensitivity
and specificity required to diagnose HE [227].
If the diagnosis of HE is difficult, neurophysiological or neuropsychological tests
can also be performed. In HE, a characteristic, slow triphasic wave is observed during
electroencephalography (EEG) [228]. This slow triphasic wave is an overall periodic
waveform in the bilateral frontal lobes that demonstrates bilateral synchronization
and is often accompanied by slow background activity; it is usually seen in phase
2 or 3 HE and disappears in comatose patients [225,229]. Once a slow triphasic wave
has developed, the clinical outcome is reportedly very poor [230]. In recent studies,
the decrease in EEG amplitude in patients with OHE was associated with the severity
of HE [231].
The brainstem auditory-evoked-potential test is sensitive for the diagnosis of CHE
[226,227,232]. Patients with liver cirrhosis accompanied by CHE exhibit conduction
time delays (I–V latency) from the auditory nerve to the midbrain and conduction time
delays (III–V latency) from the pontine to the midbrain on the brain auditory-evoked-potential
test. It is also known that the risk of developing OHE is increased when abnormal
findings are observed on the brain auditory-evoked-potentials test [227]. However,
in a study using the cortical auditory-evoked-potential test, the N200 latency was
increased in patients with HE [233]. Therefore, the diagnosis of HE cannot be made
using EEG alone; further research is required to determine the usefulness of evoked-potential
EEG in the diagnosis and prognosis of HE.
Serum ammonia
The venous blood ammonia level is not proportional to the degree of HE and has no
association with its prognosis [234]. The metabolism of ammonia is greatly influenced
by various organs, such as the kidneys, muscles, brain, and bowel, as well as the
liver [235]. However, repeated measurements of ammonia concentrations can help to
determine a treatment’s effects [235,236]. If patients with suspected OHE have normal
ammonia concentrations, attention should be paid to the differential diagnosis to
look for other diseases [234]. There are various methods of measuring ammonia concentrations,
such as those involving the venous or arterial blood or plasma. Because the normal
range varies depending on the specific measurement method, a suitable reference value
should be used. Although the partial pressure of ammonia gas in arterial blood is
thought to be closely related to both the neurophysiological test results and the
ammonia concentration in the blood–brain barrier in patients with HE, additional studies
are needed to determine the clinical usefulness of that value [237]. Regarding other
serum markers, some studies have reported increases in the serum S100β concentration
that were proportional to the cognitive function test results in HE patients [238].
[Recommendations]
1. To confirm the diagnosis of OHE, other diseases that can cause cognitive impairment
must first be ruled out, and the diagnosis must be made based on clinical symptoms.
(A1)
2. HE is classified as either OHE, which can be diagnosed using only symptoms, or
CHE, which requires a cognitive function test. (B1)
3. In patients with suspected HE, imaging tests, including a brain MRI or a neurophysiological
test, can be performed to rule out other diseases that can cause cognitive impairment
.(B2)
4. Venous blood ammonia levels are not proportional to the degree of HE and are not
associated with its prognosis (A1). However, if patients with suspected HE show normal
ammonia concentrations, differentiation from other diseases is required. (B1)
Management of overt HE
The goals of treatment
The goals of treatment are as follows: 1) prevention of secondary damage caused by
decreased consciousness and normalization of the patient’s state of consciousness,
2) elimination of social and economic restrictions by preventing recurrence, and 3)
improvement of patient prognosis and quality of life. Therefore, appropriate supportive
care should be provided to prevent secondary damage (e.g., fall-related injuries or
aspiration pneumonia) from an altered consciousness. Furthermore, the precipitating
factors should be identified and managed appropriately as soon as possible, and treatments
should be initiated using medications that can decrease or eliminate the production
of ammonia, the major pathogenic material.
Identification of precipitating factors and management
The precipitating factor can be identified in 80–90% of patients with HE [239]. In
many cases, HE can be improved simply by eliminating the precipitating factor; therefore,
identifying and promptly managing the precipitating factors is required [240]. The
currently known precipitating factors of HE and the corresponding diagnostic tests
and treatments are shown in Table 4. According to reports from patients in the Republic
of Korea [241,242], gastrointestinal bleeding, infection, dehydration by paracentesis,
and constipation were the major precipitating factors.
Management of overt HE
Non-absorbable disaccharides
The primary treatment for HE is nonabsorbable disaccharides such as lactulose (β-galactosido-fructose)
or lactitol (β-galactoside sorbitol), which lead to recovery in 70–90% of HE patients
[217]. Therapeutic mechanisms involve the reduction of intestinal pH by the production
of acetic and lactic acids (via bacterial degradation of lactulose). Another potential
mechanism is the ability of the nonabsorbable disaccharides to increase the count
of lactobacillus, which do not produce ammonia. Furthermore, nonabsorbable disaccharides
convert ammonia to ammonium, rendering it less absorbable, and they also produce an
osmotic laxative effect that flushes the ammonia out [93,217]. Based on many clinical
studies and their low cost, nonabsorbable disaccharides are recommended as an initial
therapeutic opition [209,240]. Uribe et al. [243] found that a 20% lactitol enema
had higher efficacy in improving symptoms than a tap water enema (100% vs. 20%, P=0.0037)
and that the overall response rate to nonabsorbable disaccharides–based therapy was
82.5%. According to a systematic review and meta-analysis [244], lactulose or lactitol
was more effective in improving symptoms than placebo, with a RR of 0.62 (95% CI,
0.46–0.84), This finding was reproduced in another recent study [245], which found
an RR of 0.63 (95% CI, 0.53–0.74). When overt HE occurs, 30–45 mL of lactulose (20–30
g) every 1–2 hours should be administered orally until the patient is having at least
2 bowel movements a day. An equivalent daily dose of lactitol is 67–100 g [246]. Thereafter,
the dose should be titrated to achieve two to three soft stools per day. If patients
are unable to take medications orally, administration via nasogastric tube might be
tried. If patients have severe HE (West-Haven criteria of grade 3 or more) or are
unable to take medications orally or via nasogastric tube, an enema of 300 mL lactulose
and 700 mL water can be performed 3–4 times per day until clinical improvement is
noted [240,243,247,248]. In this situation, the enema solution should be retained
in the intestine for at least 30 minutes [93].
Non-absorbable antibiotics
Rifaximin, a rifamycin derivative, maintains high concentration levels in the intestine
because it is not absorbed, and it remains in an active form until it is excreted.
It inhibits bacterial RNA synthesis by binding to bacterial DNA-dependent RNA polymerase,
and it has broad antimicrobial activity against aerobic and anaerobic gram-positive
and gram-negative bacteria [93]. So far, several studies have shown that rifaximin
has a positive effect in managing HE [242,249-251]. Several RCTs with small sample
sizes have assessed the effect of rifaximin as a first-line regimen for OHE. A meta-analysis
of those RCTs found that rifaximin had a therapeutic effect similar to that of lactulose
or lactitol [249,251-254]. Furthermore, in a recent RCT, patients treated with a combination
of rifaximin and lactulose showed a better recovery from HE within 10 days (76% vs.
44%, P=0.004) and shorter hospital stays (5.8 vs. 8.2 days, P=0.001) than those treated
with lactulose alone [255]. The maximum dose is 1,200 mg/day, which might limit its
use in cases of severe HE (West-Haven criteria of grade 3 or more) because of the
need for oral administration [93].
Neomycin and metronidazole are also poorly absorbed by the intestine, affect urea-producing
bacteria, and reduce the generation of ammonia, which improves HE [93]. However, they
are not recommended for the management of HE because of their side effects, such as
intestinal malabsorption, nephrotoxicity, and ototoxicity for neomycin and peripheral
neuropathy for metronidazole [209,240,256].
LOLA
Because ornithine and aspartate are important substrates used to metabolize ammonia
to urea and glutamine, the administration of LOLA can lower plasma ammonia concentrations,
with produces improvements in HE [93,257]. For patients with West-Haven criteria grade
1–2 HE, intravenous LOLA can lower the number connection test (NCT)-A time and plasma
ammonia concentrations more effectively than placebo [258]. According to a recent
RCT, patients treated with the combination of lactulose and intravenous LOLA (30 g/day)
had a lower grade of HE within 1–4 days of treatment, with an OR of 2.06–3.04 and
a shorter duration until symptom recovery (1.92 vs. 2.50 days, P=0.002), compared
with those who received lactulose alone [259]. Oral LOLA can lower the NCT-A time
and plasma ammonia concentrations; [260,261] however, further studies are required
to assess its efficacy in managing OHE [257].
Branched-chain amino acids (BCAAs)
Among cirrhotic patients, the capacity for glycogen storage in the liver decreases
along with the reduced liver parenchyme. Therefore, catabolism becomes predominant
because protein is required for gluconeogenesis. Because BCAAs, such as valine, leucine,
and isoleucine, are absorbed in the peripheral tissue, patients with cirrhosis have
a lower concentration of the BCAAs and a higher concentration of the aromatic amino
acids in the blood compared with healthy people. Thus, BCAA supplementation inhibits
proteolysis and decreases the influx of toxic materials via the blood-brain barrier.
Furthermore, it plays an important role in muscle metabolism, leading to glutamine
production that is useful for detoxifying ammonia [262,263]. According to recent meta-analyses
[264-266], oral BCAAs might be beneficial in managing OHE and should be used as an
ancillary pharmacological option. However, intravenous BCAAs have no effect on episodic
HE [209,240,267].
Others
Because albumin has great anti-inflammatory and immunomodulatory properties, it might
be helpful in improving the overall survival time of patients with decompensated liver
cirrhosis [268-270]. According to recent research in patients with West-Haven criteria
grade ≥2 HE [271], those treated with a combination of lactulose and intravenous albumin
(1.5 g/kg/day) showed a better recovery rate within 10 days than those treated with
lactulose alone (75% vs. 53.3%, P=0.03) (Table 5).
In addition, polyethylene glycol (PEG), an osmotic laxative, might be tried. Its postulated
mechanism of action is flushing ammonia out of the gut, like the nonabsorbable disaccharides
[240]. A single RCT comparing PEG (4 liters over 4 hours via oral administration or
nasogastric tube) to lactulose only showed it to be superior in terms of clinical
improvement over a 24-hour period, documented by a greater decrement in the HE scoring
algorithm (Δ 1.5 vs. Δ 0.7, P=0.002) and a shorter median time to resolution (1 day
vs. 2 days, P=0.01) [272]. However, further studies are required to assess its efficacy
and safety.
Flumazenil, an antagonist of the benzodiazepine receptor, might improve consciousness
among patients with severe HE; however, its effect is temporary, and survival time
is not improved [273]. Therefore, it is not recommended as a first-line regimen. Nonetheless,
it can be used in patients with HE caused by benzodiazepine. Levocarnitine or sodium
benzoate might be effective in managing HE because they can lower plasma ammonia concentrations
[274,275].
Liver transplantation
Patient with acute liver failure and HE can be considered for liver transplantation
because of their poor prognosis [93]. In cases of recurrent OHE, the severity is associated
with its overall prognosis [276], and the overall survival rate after an episode of
OHE was 42% and 23% at 1 and 3 years, respectively [277]. Therefore, liver transplantation
should be considered for such patients. Furthermore, liver transplantation is also
indicated in patients with severe HE who do not respond to the above medical treatments.
[Recommendations]
1. Precipitating factors of HE include gastrointestinal bleeding, infection, constipation,
infection, excessive intake of protein, dehydration, renal function disorder, electrolyte
imbalance, psychoactive medication, and acute hepatic injury. So first, those factors
should be recognized and managed. (A1)
2. To manage acute episodic over t HE, non-absorbable disaccharides (e.g., lactulose,
lactitol) are recommended. Enema is recommended in severe HE (West Haven criteria
grade ≥3) or a clinical situation in which oral intake is inappropriate. (A1)
3. Rifaximin might be combined with non -absorbable disaccharides to treat patients
with HE. (B1)
4. Oral BCAA and intravenous LOLA or albumin can be used additionally. (B2)
5. Liver transplantation is indicated in patients with severe HE who do not respond
to the medical treatments. (A1)
Prevention of overt HE
Medical therapy
Among patients with OHE, 50–70% will experience a recurrence within 1-year, so secondary
prevention for OHE should be started after the first event. As the first-line therapy,
nonabsorbable disaccharides (lactulose [278,279], lactutol [280]) should be used.
A dose of 30–60 mL of lactulose, allowing 2–3 stools per day, in patients who recovered
from acute episodes of OHE significantly reduced the recurrence of OHE (19.6%) compared
with the control group (46.8%) [278]. In cases of lactulose/lactitol intolerance,
rifaximin can be used as single therapy (400 mg tid or 550 mg bid) [281]. According
to a case-control study that included decompensated liver cirrhosis patients, a median
2 years of rifaximin therapy significantly lowered the recurrence of OHE compared
with the control group (31.5% vs. 47%, P=0.034) [281].
A prospective RCT by Bass et al. [282] found that 6-months of rifaximin therapy significantly
lowered the recurrence of OHE compared with the placebo group (hazard ratio [HR],
0.42; 95% CI, 0.28–0.64); about 91% of that study population used lactulose concomitantly.
Non-absorbable disaccharide and rifaximin combination therapy can reduce the recurrence
of OHE more than each single therapy [240,282], and it is therefore recommended for
recurrent OHE. These medical treatments can effectively prevent OHE recurrence and
improve the survival times of patients with OHE [281,283]. Long-term treatment with
rifaximin raised concerns about the risk of Clostridium difficile (C. difficile) infection,
but recent studies found that C. difficile infection was not increased by rifaximin
treatment compared with the control group [283-285].
Long-term oral BCAA treatment is recommended for patients whose oral diet is insufficient
because it can improve symptoms and reduce the recurrence of OHE [266,286]. In a meta-analysis
of 16 RCTs, oral BCAA reduced the recurrence of OHE (HR, 0.73; 95% CI, 0.61–0.88),
but the overall survival time did not differ between the two groups [266].
LOLA can reduce the recurrence of HE. In an RCT including 150 patients, oral LOLA
(6 g three times per day) for 6 months significantly reduced the recurrence of OHE
(HR, 0.39; 95% CI, 0.17–0.87) [287]. Nonetheless, recent meta-analyses have shown
that oral LOLA was not more effective than lactulose or rifaximin for OHE prevention
[287,288].
In patients with intractable ascites, intravenous albumin infusion can prevent OHE.
A recent prospective RCT showed that long-term intravenous albumin (40 g per week)
infusion significantly lowered the risk of grade 3 or 4 OHE (HR, 0.48; 95% CI, 0.37–0.63)
and improved overall survival times (HR, 0.62; 95% CI, 0.40–0.95) [269].
Education
A structured educational intervention has been reported to improve patient adherence
to prophylactic therapy and reduce readmission with OHE [289]. According to an RCT
of 39 patients with a history of OHE, a 15-minute educational session reduced the
risk of OHE-related hospitalization (HR, 0.14; 95% CI, 0.02–0.77) [269]. The education
of patients and caregivers should include 1) the effects and potential side effects
(e.g., diarrhea) of the prescribed medication (lactulose, rifaximin, and so on), 2)
the importance of adherence, 3) early symptoms and signs of recurring OHE, and 4)
actions to be taken if a recurrence begins [209].
Nutritional management and exercise
Nutritional deficits and subsequent sarcopenia are known to increase complications,
including HE [290,291], and lower the overall survival times of cirrhotic patients
[292-294]. Therefore, adequate assessment and intervention for nutritional status
are recommended. Because most decompensated cirrhotic patients are malnourished, daily
energy intake should be 35–40 kcal/kg, and protein intake should be 1.2–1.5 g/kg.
Long-term protein restriction should be avoided because it can induce protein catabolism,
hepatic dysfunction, and sarcopenia [295].
To take in enough energy, small frequent meals (4–6 times per day including a night
snack) improve the long-term prognosis for liver cirrhosis patients while preventing
sarcopenia [296], but the direct effect that small meals and a night snack has on
OHE prevention has not been fully established.
Exercise can improve the long-term outcomes of cirrhotic patients [297,298]. In particular,
cirrhotic patients usually have decreased skeletal muscle volume [291] because hyperammonemia
hinders the synthesis of skeletal muscles [299,300]. An adequate exercise program
can prevent muscle loss [301], enhance effective ammonia metabolism, and prevent OHE
recurrence. However, exercise can temporarily increase the portal pressure in OHE
patients [297,298], and it could increase the risk of a fall or fracture in malnourished
patients. Therefore, adequate nutritional support should precede exercise therapy
(Fig. 5).
[Recommendations]
1. A nonabsorbable disaccharide (lactulose, lactitol) or rifaximin, as single or combined
therapy, is recommended for the prevention of overt HE recurrence. (A1)
2. Oral branched-chain amino acid or oral LOLA supplementation can prevent the recurrence
of overt HE. (B1)
3. Adequate education of patients and caregivers at the time of discharge is needed
to reduce the recurrence of overt HE. (B1)
4. Nutritional assessment and management are needed for decompensated liver cirrhosis
patients who experienced overt HE. (B1) Long-term protein restriction should be avoided,
and adequate energy and protein intakes are necessary. (B1)
Covert HE
Definition
CHE is regarded as the preclinical stage of OHE, and it includes West-Haven criteria
grade 1 and MHE, which is the mildest form of HE [210]. It is difficult to diagnose
CHE it because it can be diagnosed only by psychometric or neurophysiologic examination
and is without definite clinical manifestations, such as disorientation or asterixis.
Furthermore, it is difficult to clinically distinguish MHE and grade 1 HE. Therefore,
MHE and grade 1 HE from the West-Haven criteria are often defined as a single syndrome
called CHE. Because the concept of CHE was initiated by ISHEN in 2011, most previous
studies have been done on MHE; little research has been done on CHE, including West-Haven
criteria grade 1 HE [210].
The prevalence of MHE is 22–78% of patients with liver cirrhosis, although the rate
can differ depending on the diagnostic method [226,302-308]. The prevalence of MHE
is related to prior episodes of OHE, age, severity of liver disease, and the presence
of EVs [309]. In a study using the psychometric HE score (PHES) in a single institution
in Korea, MHE was seen in 25.6% of patients with cirrhosis, including 20.2% of those
in Child-Pugh A, 42.9% in Child-Pugh B, and 60% in Child-Pugh C [310].
Clinical significance
Patients with CHE have impaired cognitive functions such as attention, executive functions,
visuospatial perception, psychomotor speed, and reaction times [311]. Those impaired
cognitive functions interfere with daily functioning, such as social interactions,
alertness, emotional behavior, sleep, home management, and recreation, and lower the
quality of life [214,304,312].
Patients with CHE are at risk of falls and fractures [313,314], and their poor cognitive
performance increases the risk that they will lose their jobs [315]. Therefore, CHE
increases the burden on both individual patients and society. CHE is regarded as the
preclinical stage of OHE because of the increased risk of progression to OHE [226,302],
and CHE is associated with worsened survival times [316,317]. However, it is difficult
to distinguish whether the shortened survival is caused by CHE or hepatic dysfunction.
Diagnosis
To diagnose CHE, the patient must have 1) a disease that can lead to CHE, such as
liver cirrhosis or a portosystemic shunt, 2) no other neurological disease, 3) no
neurological manifestation such as disorientation or asterixis, and 4) abnormal cognitive
or neurophysiologic functioning.
Paper and pencil testing
One of the paper and pencil tests, PHES, consists of five tests (digit symbol test,
NCT-A, NCT-B, serial dotting, and line tracing) that measure attention, psychomotor
speed, visual perception, and visuo-spatial orientation [318]. The PHES has been widely
used to diagnose CHE and has a sensitivity of 96% and a specificity of 100% [319].
It was developed in Germany and has been validated in several countries, including
Korea [310,319-324]. It is recommended that at least two of the NCT-A, NCT-B, block
design test, and digit symbol test be performed if the full PHES cannot be used due
to copyright issues or in places where the PHES has not been validated [208].
The Korean paper and pencil test (KPPT) to evaluate MHE in Korean patients with liver
cirrhosis was developed with the support of the Korean Association for the Study of
the Liver [325,326]. The KPPT consists of six tests: NCT-A, NCT-B, digit span test
(DST), symbol digit modality test (SDMT), word list memory test, and Medical College
of Georgia Complex figures. The KPPT short version is configured to be relatively
simple to use and contains the NCT-A, NCT-B, DST, and SDMT. A recent prospective multicenter
study validated the KPPT short version in Korean patients with liver cirrhosis [325].
The KPPT is available at http://encephalopathy.or.kr/inspection [326].
Computerized testing
Inhibitory control test (ICT)
The ICT is a computerized test that evaluates attention, response inhibition, and
working memory [306,327]. In the ICT, the subject is instructed to respond to alternating
patterns of the letters X and Y, called the target. Non-alternating presentations
of the letters X and Y, called lures, are randomly planted within the sequence of
letters. This test evaluates the response times of the subjects and the response rate
to the target and lures. The sensitivity and specificity of the ICT are 87% and 77%,
respectively, and it is highly reproducible [327]. However, it has not been validated
for Korean patients.
Stroop test
The Stroop test evaluates psychomotor speed and cognitive flexibility [328] using
two components (the “off” and “on” states). In the “off” state, subjects match the
color of the symbol. In the “on” state, subjects match the color of the word when
the color of the word and the meaning of the word are incongruent, which evaluates
response inhibition.
The computer-based Stroop test shows a sensitivity of 89.1% and a specificity of 82.1%
when using the paper and pencil test as a standard test [329]. A recent prospective
multicenter study in the US showed that Stroop test had high sensitivity and acceptable
inter-center agreement [330]. In addition, the Stroop test has good test–retest reliability,
and it has the advantage that it can be easily administered using a smartphone. A
Korean Stroop test was developed, and a recent study showed that the Korean Stroop
test is valid for diagnosing MHE (area under the curve, 0.74; 95% CI, 0.66–0.83, P<0.001)
[331]. The Korean Stroop test is available at http://encephalopathy.or.kr/inspection
[326].
Neurophysiological testing
EEG
EEG is a test that reflects cerebral cortical neuronal activity. In patients with
CHE, a quantitative EEG analysis shows an increase in the relative power of the θ
band and a decrease in the mean dominant frequency [332]. However, EEG can be affected
by various conditions that can affect cortical function. In addition, it requires
a technician and a neurologist and is associated with both interobserver and intraobserver
variability.
Critical flicker frequency (CFF)
CFF measures the frequency at which light begins to flicker noticeably. CFF is highly
correlated with paper and pencil testing [333]. In a meta-analysis of nine studies
using CFF, the sensitivity and specificity for diagnosing CHE were 61% and 79%, respectively
[334]. However, it is not applicable to patients with red-green blindness or Korean
patients with cirrhosis because it has not been validated in Korea.
Other tests
The animal naming test (ANT) is a semantic fluency test that consists of listing the
names of as many animals as possible in 1 minute. In a prospective study conducted
in Italy, the sensitivity and specificity of the ANT for diagnosing CHE were 78% and
63%, respectively, when the cut-off was less than 15, and the ANT was a significant
predictor for the development of OHE [307]. In a recent prospective study in Germany,
the sensitivity and specificity were 31% and 98%, respectively, when the cut-off was
less than 15, and they suggested 23 as a cut-off to increase sensitivity [335]. Nabi
et al. [336] reported that a combination of age, sex, and the responses to 4 Sickness
Impact Profile (SIP) questions that are highly related to CHE identified patients
with CHE with more than 80% sensitivity. However, that test needs to be validated
further. Some studies reported that serum cytokines, such as interleukin (IL)-6, IL-17a,
interferon-γ [337-339] and 3-nitrotyrosin [340,341], are associated with CHE. However,
further studies are needed on the pathophysiology of CHE and the role of the markers
in CHE.
Diagnosis and screening
CHE has no clinical signs of HE. It can show abnormalities in cognitive functions
in various fields, but each field is not reduced to the same extent. In addition,
because one test cannot judge the abnormality in all fields and agreement is poor
between tests [342,343], a combination of least two tests is recommended for a diagnosis
of CHE [210]. For multicenter studies, a paper and pencil test and one computerized
or neurophysiologic test are recommended for a CHE diagnosis. A single institution
can use one test that has been validated locally [209].
Because CHE decreases patient quality of life, increases socioeconomic burden, and
hastens mortality, it might be necessary to test and diagnose all patients at risk.
However, that would increase costs. Therefore, it is advisable to perform a diagnostic
test in patients with a history recent of falls or traffic accidents and patients
who report a low quality of life or complaints about daily living, such as those who
complain of sleep disturbance or a loss of concentration or memory [209,344].
Because most patients with CHE are diagnosed at an outpatient clinic, the screening
tests should be performable without any special tools and with high sensitivity, such
as the four questions from SIP, the ANT, and the Stroop test using a smartphone.
Treatment
Most studies about treating CHE were performed in a small number of patients with
a short duration of treatment. In addition, most studies have focused on improving
cognitive function and quality of life; studies are still needed on extending survival
and reducing readmissions or the development of OHE.
As with OHE, it is known that nitrogenous substances, especially ammonia, play a major
role in CHE. Therefore, treatments can be given to reduce ammonia. The most studied
treatment is lactulose, which showed a marked improvement in cognitive function and
quality of life [304,345] and decreased the development of OHE [345], compared with
the placebo.
Probiotics alter the gut microbiome and inhibit ammonia production in the intestine,
thereby improving cognitive function and decreasing the development of OHE [346-348].
However, studies on the effects of probiotics in patients with CHE have low evidence
levels [349]. Additional studies are needed to determine the beneficial probiotic
species and optimal doses. Rifaximin and nonabsorbable antibiotics also improved cognitive
function and quality of life [305] and improved driving ability [350]. However, rifaximin
failed to establish non-inferiority over lactulose in non-inferiority studies [351],
and lactulose treatment is more cost-effective than rifaximin therapy [350]. Therefore,
further studies on the role of rifaximin in the treatment of CHE are warranted. Although
LOLA [352], BCAA [353], acetyl L-carnitine [354,355], and nutrition therapy [308]
have been reported to improve cognitive function, there is still a lack of evidence
for those treatments.
[Recommendations]
1. In patients with liver cirrhosis, the KPPT or the Korean Stroop test can be used
to diagnose CHE. (B2)
2. Treatment with lactulose (B1) or rifaximin (B2) can be used to improve cognitive
function and quality of life in patients with CHE.
HE and health-related quality of life (HRQoL)
HRQoL in patients with cirrhosis is lower than that of patients with chronic liver
disease without cirrhosis. The HRQoL of cirrhotic patients with HE is particularly
low [356]. Patients with HE suffer from various degrees of altered consciousness,
personality changes, impaired intellectual functioning, and neuromuscular dysfunction.
Although HE is not immediately life-threatening, it can greatly interfere with a patient’s
functioning, social interactions, and sense of well-being [357]. The occurrence of
HE is associated with various complications that can also adversely affect HRQoL.
Therefore, the independent effect of HE on HRQoL is not easily measured. Because patients
with OHE are unaware of their disease (anosognosia) [358], alterations in their behavior
and abilities are more easily recognized by the people living with them than by the
patients themselves. The presence of OHE negatively affects both mental and physical
functioning, whereas MHE mainly has negative effects on mental health. Several studies
have shown that the HRQoL of patients with MHE is lower than that of patients without
HE [312,359-362]. Therefore, we suggest that patients with cirrhosis should be screened
for the early detection and treatment of HE to improve their HRQoL.
Measuring of health-related quality of life in patients with HE
HRQoL is measured using self-administered, standardized questionnaires in which patients
report their health status. The questionnaires are classified as generic and disease-specific
[363]. Because generic questionnaires provide an overview of HRQoL, usually taking
into account the physical, mental, and social aspects of a patient’s health status,
generic questionnaires have the advantage of depicting the relative impacts of different
diseases. However, generic questionnaires have the disadvantage of insensitivity to
clinically important changes. Thus, generic questionnaires are often combined with
disease-specific questionnaires. The most widely used generic questionnaires for measuring
HRQoL are the SIP, Nottingham Health Profile (NHP), and Medical Outcomes Study Short
Form-36 (SF-36) [364]. The SIP consists of 136 items that measure 12 domains. It requires
several minutes to complete, and patients with cognitive dysfunctions sometimes fail
to complete it [365]. The NHP measures distress and is useful in patients with moderate
or severe disability, but it is not very sensitive to mild disability [366]. The SF-36
is applicable to a wide range of patients, from those with a severe disability to
the general population. The SF-36 is easy to complete and has high sensitivity, which
makes it the best and most widely used scale in clinical practice. It contains 36
questions that are split into eight domains and provides a physical component summary
(PCS) and a mental component summary (MCS) (Supplementary Table 1) [367].
Disease-specific questionnaires have been developed for a variety of chronic diseases,
such as renal failure, heart failure, liver cirrhosis, diabetes, and osteoarticular
diseases, that greatly affect the HRQoL of patients. Liver-disease-specific questionnaires
include the Chronic Liver Disease Questionnaire (CLDQ), Liver Disease Quality of Life
(LDQOL), Short Form Liver Disease Quality of Life (SF-LDQOL), and Liver Disease Symptom
Index 2.0 (LDSI). The CLDQ comprises 29 questions split into six domains, with domain
scores and an overall score presented as 1–7 scales. Higher scores on the CLDQ represent
better HRQoL. The CLDQ is short, easily applicable, and correlates with the severity
of liver disease [368]. The LDQOL uses the SF-36 and adds 12 liver-specific scales
comprising 75 questions. All scales are scored from 0–100, with higher scores representing
better HRQoL [369]. The SF-LDQOL uses the SF-36 and adds 36 Likert questionnaires;
it is also scored from 1–100 [370]. The LDSI uses 18 items to measure the impact and
severity of a patient’s liver disease on daily activities in nine areas (Supplementary
Table 2) [371].
Influence of HE on health-related quality of life
Although there is a large consensus about the direct and profound effect that HE has
on HRQoL, most studies have focused on MHE [208,372,373]. A small study about the
HRQoL of patients with and without HE compared 18 patients experiencing OHE with 57
patients without a previous episode. Patients with a previous episode of OHE had significantly
low SF-36 PCS and MCS scores. However, patients with MHE were affected in only one
domain, physical functioning, of the SF-36 [374]. One study of 160 cirrhotic patients
undergoing liver transplantation found that patients with MHE or OHE had a lower MCS
than patients without HE [357].
Cognitive impairment of patients with HE mainly affects areas that require multiple
and complicated functions, such as attention, visuospatial abilities, psychomotor
speed, balance, and coordination, rather than language or general intellect. In other
words, patients can perform daily activities such as wearing clothes or using the
toilet, but their overall planning or cognitive function and exercise performance
might suffer [318]. Because driving a vehicle requires comprehensive performance and
a strategic way of thinking, patients with MHE require attention while driving [375-378].
Cirrhotic patients engaged in professions that required sustained attention and motor
coordination are more severely affected by MHE than those with jobs that require mainly
verbal abilities. In an outpatient cohort with cirrhosis, up to 60% of blue collar
workers lost their jobs, versus only 20% of white collar workers [236].
A disruption of normal sleep-wake patterns is another early sign of HE [379], and
regular sleep is a key indicator of perceived health status. Sleep disturbances are
included as relevant items in the assessment of HRQoL in the NHP questionnaire, and
sleep disturbances in patients with HE negatively affect HRQoL [380]. Patients with
MHE report a decrease in the quality of their sleep and in their physical and mental
HRQoL [214,381].
Psychological status and a patient’s mood can affect the course of a disease and treatment
response, and depression affects social functioning, physical abilities, and health
status [382]. Cirrhotic patients suffer not only from liver disease itself, but also
from decreased quality of life in the form of poor work performance and an increased
risk of accidents. Therefore, there is a need for extensive social attention and research
on public social support systems and economic support for cirrhotic patients.
Effects of treatment on HE and health-related quality of life
Although many studies have aimed at improving HE, relatively few studies have aimed
at a significant improvement in the HRQoL of patients with HE [383]. Prasad et al.
[304] first investigated the effect of treatment-related improvements in cognitive
function on HRQoL. Patients with MHE treated with lactulose for 3 months showed a
significant improvement in their HRQoL on several SIP subscores, particularly in emotional
behavior, mobility, sleep/rest, and recreation and pastimes. In an 8-week study of
rifaximin therapy in patients with MHE, the patients showed significantly improved
scores in both neuro-psychometric performance and the SIP [305]. Another study reported
that rifaximin therapy to prevent a recurrence in patients with HE favorably affected
HRQoL as measured by CLDQ scores [384]. Treating OHE patients with oral LOLA [385]
and MHE patients with acetyl-L-carnitine [354] also improved HRQoL. However, a 60-day
course of probiotic yogurt supplementation had no significant effects on HRQoL in
25 patients with cirrhosis [346].
To date, insufficient studies have been done to establish an association between improved
HRQoL and treatments for OHE and MHE. Considering that 10% or more of cirrhotic patients
have HE, and 50% of cirrhotic patients with MHE who have not been treated can progress
to OHE within 4–24 months [386], it is necessary to change the paradigm of treatment
to improve the HRQoL of patients.
[Recommendations]
1. Active diagnosis and treatment of HE improves patient’s health-related quality
of life. (A1)
2. Health-related quality of life in patients with HE is assessed by self-administered,
standardized questionnaires and can be measured using either generic or disease-specific
questionnaires. (B2)