The Korean Journal of Hepatology 2012;18:1-21
pISSN: 1738-222X eISSN: 2093-8047
Revision and update on clinical practice guideline
for liver cirrhosis
Ki Tae Suk1, Soon Koo Baik2*, Jung Hwan Yoon3*, Jae Youn Cheong4, Yong Han Paik5,
Chang Hyeong Lee6, Young Seok Kim7, Jin Woo Lee8, Dong Joon Kim1, Sung Won Cho4,
Seong Gyu Hwang9, Joo Hyun Sohn10, Moon Young Kim2, Young Bae Kim11, Jae Geun Kim12,
Yong Kyun Cho5, Moon Seok Choi5, Hyung Joon Kim13, Hyun Woong Lee13, Seung Up Kim14,
Ja Kyung Kim14, Jin Young Choi15, Dae Won Jun16, Won Young Tak17, Byung Seok Lee18,
Byoung Kuk Jang19, Woo Jin Chung19, Hong Soo Kim20, Jae Young Jang21, Soung Won Jeong21,
Sang Gyune Kim7, Oh Sang Kwon22, Young Kul Jung22, Won Hyeok Choe23, June Sung Lee24,
In Hee Kim25, Jae Jun Shim26, Gab Jin Cheon27, Si Hyun Bae28, Yeon Seok Seo29,
Dae Hee Choi30, and Se Jin Jang31 (random order)
1Department of Internal Medicine, Hallym University College of Medicine, Chuncheon; 2Department of Internal
Medicine and Cell Therapy and Tissue Engineering Center, Yonsei University Wonju College of Medicine, Wonju;
3Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine,
Seoul; 4Department of Internal Medicine, Ajou University College of Medicine, Suwon; 5Department of Internal
Medicine, Sungkyunkwan University College of Medicine, Seoul; 6Department of Internal Medicine, Catholic
University of Daegu College of Medicine, Daegu; 7Department of Internal Medicine, Soonchunhyang University
Hospital Bucheon, Soonchunhyang University College of Medicine, Bucheon; 8Department of Internal Medicine,
Inha University College of Medicine, Incheon; 9Department of Internal Medicine, Cha University College of
Medicine, Seongnam; 10Department of Internal Medicine, Hanyang University Guri Hospital, Hanyang University
College of Medicine, Guri; Departments of 11Pathology and 12Radiology, Ajou University College of Medicine,
Suwon; 13Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul; Departments of
14Internal Medicine and 15Radiology, Yonsei University College of Medicine, Seoul; 16Department of Internal
Medicine, Hanyang University Seoul Hospital, Hanyang University College of Medicine, Seoul; 17Department of
Internal Medicine, Kyungpook National University College of Medicine, Daegu; 18Department of Internal Medicine,
Chungnam National University College of Medicine, Daejeon; 19Department of Internal Medicine, Keimyung
University College of Medicine, Daegu; 20Department of Internal Medicine, Soonchunhyang University Hospital
Cheonan, Soonchunhyang University College of Medicine, Cheonan; 21Department of Internal Medicine,
Soonchunhyang University Hospital Seoul, Soonchunhyang University College of Medicine, Seoul; 22Department of
Internal Medicine, Gachon University of Medicine and Science, Incheon; 23Department of Internal Medicine,
Konkuk University College of Medicine, Seoul; 24Department of Internal Medicine, Inje University College of
Medicine, Goyang; 25Department of Internal Medicine, Chonbuk National University College of Medicine, Jeonju;
26Department of Internal Medicine, Kyung Hee University College of Medicine, Seoul; 27Department of Internal
Medicine, Ulsan University College of Medicine, Gangneung; 28Department of Internal Medicine, The Catholic
University of Korea College of Medicine, Seoul; 29Department of Internal Medicine, Korea University College of
Medicine, Seoul; 30Department of Internal Medicine, Kangwon National University College of Medicine,
Chuncheon; 31Department of Preventive Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
Keywords: Liver cirrhosis; Clinical practice guideline
Received February 12, 2012; Accepted March 5, 2012
Abbreviations: CHB, chronic hepatitis B; CHC, chronic hepatitis C; EVL, endoscopic variceal ligation; EVO, endoscopic variceal obturation; GOV,
gastroesophageal varices; IGV, isolated gastric varices; LC, liver cirrhosis; LOLA, L-ornithine-L-aspartate; PMN, polymorphonuclear leukocyte;
SBP, spontaneous bacterial peritonitis; TIPS, transjugular intrahepatic portosystemic shunt
Soon Koo Baik
Division of Gastroenterology & Hepatology, Department of Internal Medicine and Cell Therapy and Tissue Engineering Center, Yonsei University
Wonju College of Medicine, 162 Ilsan-ro, Wonju 220-701, Korea
Tel. +82-33-741-1229, Fax. +82-33-741-1228, E-mail; email@example.com
Jung Hwan Yoon
Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu,
Seoul 110-744, Korea
Tel. +82-2-2072-2731, Fax. +82-2-743-6701, E-mail; firstname.lastname@example.org
Copyright Ⓒ 2012 by The Korean Association for the Study of the Liver
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/)
which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
2 The Korean Journal of Hepatology Vol. 18. No. 1, March 2012
Table 1. Grading evidence and recommendations
High quality Further research is very unlikely to change our confidence in the estimate of effectA
Moderate quality Further research is likely to have an important impact on our confidence in the estimate of effect and
may change the estimate
Low quality Further research is very likely to have an important impact on our confidence in the estimate of effect
and is likely to change the estimate. Any change of estimate is uncertain
Strong Factors influencing the strength of the recommendation included the quality of the evidence, presumed
patient-important outcomes, and cost
Weak Variability in preferences and values, or more uncertainty. Recommendation is made with less
certainty, higher cost or resource consumption
Liver cirrhosis (LC) is a disease with a high rate of
prevalence and one of the most common causes of mortality
in the Republic of Korea (hereafter "Korea"). In Korea,
the main etiologies of LC have been found to be chronic
hepatitis B (CHB), alcohol, and chronic hepatitis C (CHC).
In patients with complications such as ascites, variceal
bleeding, and encephalopathy, the 5-year survival rates were
32%, 21%, and 40%, respectively, reflecting the poor
prognosis of patients with LC. Consequently, a clinical practice
guideline appropriate for the medical milieu of Korea is
important for both patients and clinicians.
In 2005, the Korean Association for the Study of the Liver
established a guideline for the treatment of LC that is now
widely used. However, it is currently necessary to revise and
update the clinical practice guideline based on new evidence
over the past 6 years regarding the diagnosis, treatment, and
prevention of LC. Therefore, the Korean Association for the
Study of the Liver undertook a revision and update of
the clinical practice guideline co-organized by the Liver
Cirrhosis Clinical Research Center. This guideline was based
on an interdisciplinary (hepatology, radiology, pathology, and
preventive medicine) approach. A panel of experts selected
by the Korean Association for the Study of the Liver and
Liver Cirrhosis Clinical Research Center met several times
to discuss and write this guideline during 2005-2011. This
guideline was written in light of published studies retrieved
from MEDLINE, EMBASE, and Cochrane Library. The
panel aimed to address 5 subjects: diagnosis of LC, anti-
fibrotic therapy for LC, variceal bleeding, ascites, and hepatic
The evidence and recommendations made in this
guideline have been graded according to the GRADE
(Grading of Recommendations Assessment Development
and Evaluation) system. The strength of evidence has
been classified into 3 levels: A (high-quality evidence), B
(moderate-quality evidence), and C (low-quality evidence).
The strength of recommendation has been classified into 2
categories: strong and weak (Table 1). Where there was no
clear evidence, the recommendations were based on the
consensus expert opinion(s) in literature and that of the
1. Diagnosis of LC
LC is a pathologically defined disease, and is clinically
classified as compensated and decompensated LC. Decom-
pensated LC includes cases with ascites, variceal bleeding,
hepatic encephalopathy, or jaundice. Image studies for
diagnosing LC are CT, abdominal ultrasound, and MRI.
Typical findings of these images are nodular liver surface,
splenomegaly, and the presence of intra-abdominal collateral
vessels, which mean increasing portal venous pressure.
Although there are not established criteria for the diagnosis
of compensated LC, imaging studies may be helpful for the
diagnosis of LC b y integrating laboratory findings such as
albumin, bilirubin, or prothrombin time and platelet values.
1-1. Diagnostic approach-patient history, physical
examination, and laboratory tests
When dealing with patients with LC, evaluation of the
cause, severity, and stage is the first step. In patients with
chronic liver disease, history taking (drug use, blood transfusion,
or alcohol use), physical examination (jaundice, ascites,
Ki Tae Suk, et al. Revision and update on clinical practice guideline for liver cirrhosis 3
1. What test is needed for the diagnosis of LC in patients with
chronic liver disease?
- Find evidence for LC by history taking and physical
- In patients with chronic liver disease, to find LC, the
following tests are recommended and the findings in
parentheses should be checked. (A1)
(1) Complete blood count with platelet count
(2) Liver function test (hypoalbuminemia)
(3) Prolonged prothrombin time
(4) Imaging studies (nodularity of liver surface and
findings of LC)
(5) Endoscopy (presence of varices)
- The cause of LC should be examined including hepatitis
B virus and hepatitis C virus tests. (A1)
- The severity of LC could be assessed by Child-Pugh
classification with score. (B1)
2. Which findings are compatible with the diagnosis of LC in
the imaging studies?
- For the diagnosis of LC, compatible findings of imaging
studies (abdominal ultrasound, CT, and MRI) are
morphologic changes (nodularity of liver surface, atrophy
of the right lobe, hypertrophy of the left and caudate lobe,
expansion of the periportal space, and intrahepatic
nodule), ascites, and presence of portal hypertension
(collateral vessel or splenomegaly). (B1)
spider angioma, hepatomegaly, or splenomegaly), and symptom
such as fatigue from hepatitis should be assessed. In patients
with LC, a whole blood test including platelet count, liver
function test (albumin, aspartate aminotransferase, alanine
aminotransferase, alkaline phosphatase, and gamma glutamyl
transpeptidase), prothrombin time, abdominal ultrasound,
abdominal CT, and endoscopy should be carried out to
confirm the presence or absence of cirrhosis. In addition,
laboratory tests for hepatitis B or C virus infection are
needed for the evaluation of its cause. Generally, the Child-
Pugh score is used to assess the severity of LC. In clinical
practice for the diagnosis of LC, findings of portal hyper-
tension such as ascites, hepatic encephalopathy, or varices,
imaging findings, and laboratory findings are common
diagnostic tools. Recently, it was found that nodularity of
the liver surface, a platelet count of less than 100,000/mm3,
albumin less than 3.5 g/dL, and an international normalized
ratio of 1.3 or more are related to the presence of LC.
Presence of one condition of these findings showed a
specificity of 90.42% and a sensitivity of 61.11%.1
1-2. Imaging modalities for the diagnosis of LC
Abdominal ultrasound is safe and less expensive, and it
can be easily used as a screening test for the diagnosis of LC.
Abdominal ultrasound confirms the size of the liver,
echogenicity of the liver parenchyme, morphological
changes of the liver, ascites, and thrombus of the portal vein.
Typical ultrasound finding of LC is a coarse echo pattern by
fibrosis and regeneration. This finding ranges from mild
coarsening to visible nodules. The accuracy of CT in
diagnosing LC is 66-95%.2-6 The most important CT finding
for the diagnosis of LC is nodularity caused by regenerative
nodules, fibrosis scars, and lobar non-uniform atrophy and
hypertrophy. Nodularity of the liver surface showed a
specificity of 95%.2-4,7 Additionally, other radiologic findings
such as splenomegaly, blunt angle, morphological changes
(nodularity of liver surface, atrophy of right lobe, hypertrophy
of left and caudate lobe, expansion of periportal space, and
intrahepatic nodule), velocity of portal flow, shape of
hepatic vein waveform (Doppler test),2,4,8 and caudate
lobe/right lobe ratio (CT or MRI) are useful indices.9 If the
caudate lobe/right lobe ratio is above 0.65, it can indicate
LC, and its sensitivity, specificity, and accuracy reach 84%,
100%, and 94%, respectively.10
1-3. Pathological diagnosis of liver cirrhosis
The gold standard for confirming the diagnosis of LC is
liver biopsy, but it is invasive and susceptible to a sampling
error and inter-observer discrepancy. Therefore, liver biopsy
has not been widely used in clinical practice. Liver biopsy
can be carried out selectively for evaluating activity of the
underlying disease and fibrosis. Particularly, when cirrhosis
is diagnosed by clinical findings and imaging studies, but
not compatible with laboratory data, a liver biopsy is
especially helpful for diagnosing LC.11
The serum markers for liver fibrosis directly or indirectly
reflect extracellular matrix metabolism. However, their
clinical utility in the diagnosis of LC has not been verified.12
FibroScan has been introduced to measure liver elasticity
noninvasively and is an objective diagnostic tool for the
diagnosis of LC. However, there is no exact guideline on
how to apply it clinically, and there is some variation in its
diagnostic accuracy for the diagnosis of LC. Therefore, the
practical use of FibroScan is limited.
4 The Korean Journal of Hepatology Vol. 18. No. 1, March 2012
3. When should liver biopsy be performed in patients with
chronic liver disease for the diagnosis of LC?
- Liver biopsy should be selectively performed to detect the
cause of LC and assess the disease activity and fibrosis.
Liver biopsy is necessary on patients in whom the
diagnosis remains unclear from the conventional test (B1)
2. Anti-fibrotic therapy for LC
LC is a pathological condition of liver fibrosis generated
by continuous scar formation and recovery due to chronic
liver injury, eventually leading to the development of
regenerative nodules around the fibrotic scar.13 If liver
injury is chronically repeated, damaged liver cells cannot
regenerate and instead migrate to the extracellular matrix
such as collagen.14 The mechanism of liver fibrosis is
variable, depending on causes such as alcohol, hepatitis
virus, or bile acids. Hepatic stellate cells, which are located
in the space of Disse, play a major role in liver fibrosis.14
Histological changes associated with LC have long been
believed to be irreversible. However, in patients receiving
antiviral therapy for CHB, liver fibrosis has been observed
to be significantly improved.15 Similarly, the primary approach
to treating LC is treatment of the underlying disease. The
second approach in the treatment of LC is anti-fibrotic
therapy that targets the liver fibrosis-generating mechanism
irrespective of the cause of LC. In order to develop effective
treatments for liver fibrosis, the molecular pathogenesis
and treatment of liver fibrosis have been exhaustively
investigated over the last 2 decades. Subsequently, a number
of substances or drugs with anti-fibrotic effects in animal
experiments have been found; however, most of these have
not been verified for use in human beings.
2-1. Chronic hepatitis B
Antiviral therapy that regulates inflammation via the
inhibition of viral proliferation is recommended for improving
liver fibrosis.15-21 There were no significant differences in
the degree of improvement in fibrosis according to antiviral
drugs.22-24 As liver fibrosis progresses, the rate of improvement
by antiviral treatment increases.18,25 Therefore, in patients
with advanced liver fibrosis, antiviral treatment is needed in
the case with viral proliferation. In patients with LC due to
CHB, antiviral therapy with a sufficient treatment period
can be recommended to reduce liver fibrosis from virus
proliferation. However, in the case of drug-resistant viral
infection, the benefits of antiviral treatment are reduced.19,22,26
The extent of liver fibrosis was reduced by 49% when
treated with interferon α or peginterferon α.20 In patients
with HBeAg-positive CHB, hepatic fibrosis improved in
39% of patients after initial treatment with entecavir, whereas
in HBeAg-negative CHB, improvement was observed in
36% of patients.23,27 With 1-year tenofovir treatment, inflam-
mation improved without aggravation in 74% of HBeAg-
positive CHB patients and in 71% of HBeAg-negative CHB
2-2. Chronic hepatitis C
Interferon treatment for CHC reduces the hepatic necrotic
inflammatory reaction; particularly, in patients with a
sustained virological response, the reductions in serum
hepatitis C virus RNA and intrahepatic necrotic inflammatory
reactions are correlated.29 In particular, antiviral treatment
should be actively considered for patients presenting with
genotype 2 or 3 and a Child-Pugh score <7. In patients
with a Child-Pugh score of 7-9, antiviral treatment can be
considered with careful attention to hepatic dysfunction.30-34
Abstinence is the most important treatment of alcoholic
liver disease.35 Abstinence not only improves fibrosis in
hepatic tissue but also reduces portal pressure and inhibits
progression to LC. Ultimately, the survival rate of patients in
all stages of alcoholic liver disease increases following
abstinence, with improvements being observed in up to 66%
of patients.35 Sustained drinking increases the risk of
variceal bleeding by portal hypertension and is closely
related with mortality.
In severe alcoholic hepatitis, steroid and pentoxifylline
therapy have been recommended by several studies. However,
the effect of these drugs on fibrosis has not been confirmed;
therefore, these medications are not recommended in the
treatment of fibrosis as anti-fibrotic therapy.
2-4. Nonalcoholic fatty liver
Treatment of nonalcoholic fatty liver comprises improving
insulin resistance, removing risk factors of metabolic
syndrome, lifestyle modifications, drug therapy, and operative
treatment.36-52 Weight loss appears to help in liver steatosis
as well as relieves hepatic inflammation and fibrosis.36-39
Therefore, the first choice of therapy in nonalcoholic fatty
liver disease is weight loss through diet therapy and lifestyle
Ki Tae Suk, et al. Revision and update on clinical practice guideline for liver cirrhosis 5
1. What is anti-fibrotic therapy according to the causes of LC?
- In patients with LC, it is recommended that the cause of
disease should be treated to improve liver fibrosis. (A1)
- In patients with LC due to CHB, antiviral therapy with a
sufficient treatment period can be recommended to reduce
liver fibrosis from virus proliferation. (B1)
- In patients with LC due to CHC, antiviral therapy with a
combination of peginterferon and ribavirin can be
recommended, if the normal range of liver function with
viral proliferation. In addition, monitoring for side effects
is needed. (B1)
- In patients with alcoholic LC, strict abstinence is
recommended to prevent worsening of disease. (A1)
- In patients with nonalcoholic fatty liver disease, losing
weight, diet therapy, and exercise can be recommended.
- In patients with primary biliary cirrhosis, ursodeoxycholic
acid is recommended with a dose of 13-15 mg/kg/day.
1. What is the role of endoscopy in patients with LC?
- It is recommended that all patients undergo endoscopy
when they are first diagnosed with LC in order to
evaluate the presence of esophageal varix and the risk of
- Esophageal varices are classified into small (F1) and large
(F2 and F3). Also, red color sign should be checked during
- For patients with compensated LC should be considered
for endoscopy every 2 to 3 years, and patients with
decompensated LC every 1 to 2 years in order to evaluate
the occurrence and progression of varices. (B1)
- Patients with compensated LC with small varices not
using nonselective beta-blocker, should be considered for
endoscopy every 2 years to evaluate the progression of
- The frequency of endoscopy can be adjusted according to
the cause and progression of LC.
modifications, with more than 7% weight loss being the
recommended target.39 For nonalcoholic fatty liver disease,
clinical trials using multiple drugs have currently being
attempted. However, data regarding its effectiveness, safety,
and dosing period remain limited.40
2-5. Primary biliary cirrhosis
Ursodeoxycholic acid has been proven to improve
primary biliary cirrhosis and is the only drug recognized for
its treatment.53-56 Ursodeoxycholic acid reduces serum
bilirubin levels, which is an important prognostic factor, and
delays the progression and deterioration of fibrosis55,56
13-15 mg/kg/day is the most effective dose in terms of
biological effect and cost-effectiveness. Improvements of
liver function tests appear within 6-9 months of therapy in
more than 90% of patients.57 Ursodeoxycholic acid treatment
is not known to improve fatigue, itching, bone diseases, or
autoimmune reactions associated with primary biliary
3. Variceal bleeding
Esophageal variceal bleeding is found in approximately
40% of patients with Child-Pugh A class LC, and in
approximately 80% of patients with Child-Pugh C class
LC.58 The risk of variceal bleeding depends on the size of
varices, red color sign, and the Child-Pugh classification.
Variceal bleeding due to portal hypertension can be prevented
when the value of hepatic venous pressure gradient is lower
than 12 mmHg or when it is decreased to lower than 20% of
the baseline measurement.59
It is recommended that all patients undergo endoscopy
when they are first diagnosed with LC in order to evaluate
the presence of esophageal varix and the risk of bleeding.60
Esophageal varices are classified based on the diameter of
varices and their morphology as follows: varices with the
findings of larger than 5 mm61 or F2-F3 (beaded varices -
crystalled varices) are defined as large and varices with the
findings of smaller than 5 mm or F1 (straight varices) are
defined as small.62 Treatment to prevent esophageal variceal
bleeding should be performed when large varices are
present. For patients with compensated LC should be
considered for endoscopy every 2 to 3 years, and patients
with decompensated LC every 1 to 2 years in order to
evaluate the occurrence and progression of varix.63 Patients
with compensated LC with small varices not using
nonselective beta-blocker, should be considered for
endoscopy every 2 years to evaluate the progression of
3-2. Acute esophageal variceal bleeding
3-2-1. Definition and diagnosis
Acute variceal bleeding is defined as hematemesis within
last 24 hours of presentation, and/or ongoing melena, with
the last melenic stool within last 24 hours before the hospital
visit in a known or suspected case of portal hypertension.
6 The Korean Journal of Hepatology Vol. 18. No. 1, March 2012
Table 2. Drugs for acute esophageal variceal bleeding
Type Effect Dose, usage, duration
Terlipressin Side effect (cardiac ischemia)
Improve survival rate
Effect on hepatorenal syndrome
Inject 2 mg at first and inject 1-2 mg every 4-6 hours
until control bleeding or use for 3 days
(intestinal vessel constriction, vomiting, or hyperglycemia)
Do not improve survival rate
Somatostatin: IV 250 μg at first and 250 μg/hour for
Antibiotics Reduce bacterial infection
Improve survival rate
Ceftriaxone: IV 1g/day for 5-7 days
Norfloxacin: PO 400 mg twice a day for 5-7 days
2. How should acute variceal bleeding be treated?
- It is recommended that patients with acute variceal
bleeding initially be administered vasoconstrictor and
antibiotic treatment. (A1)
- Endoscopic treatment is recommended for patients with
acute variceal bleeding. (A1)
- TIPS can be recommended if drugs and endoscopic therapy
have failed or endoscopic treatment is impossible. (B1)
Endoscopy is the most definite diagnostic method for
identifying acute esophageal variceal bleeding. Variceal
bleeding can be diagnosed as follows: direct visualization of
blood issuing from esophageal varices, presence of signs of
recent bleeds on varices such as white nipple sign or
overlying clot, or presence of blood in the stomach in the
absence of another source of bleeding.64
The first line of therapy includes vasoconstrictors such as
terlipressin and somatostatin.65 Antibiotics are recommended
for patients admitted in the hospital.66 Antibiotic therapy is
recommended for 5-7 days to prevent sepsis and rebleeding
following endoscopy (Table 2).67
Medication and endoscopic therapy are recommended in
patients with acute variceal bleeding for the first time.68 If
active bleeding is present, banding of the culprit vessel or
that just below the ooze should be performed endoscopically.
After ligation of the active bleeding site, even in the absence
of active bleeding, banding should be performed starting
from just above the gastro-esophageal junction (5-10 mm)
in a sequential manner up to 5 cm. Endoscopic injection
sclerotherapy is recommended if endoscopic variceal ligation
is technically impossible or has failed.
Balloon tamponade can be used as a rescue therapy if
active variceal bleeding cannot be controlled. Transjugular
intrahepatic portosystemic shunt (TIPS) is recommended
if medication and endoscopic therapy have failed or if
endoscopic therapy is impossible.
3-3-1. Prevention of first bleeding in patients without
Nonselective beta-blockers are not recommended in
patients without esophageal varices.69,70
3-3-2. Prevention of first bleeding in patients with small
Nonselective beta-blockers do not lower the incidence
of bleeding in patients with small esophageal varices.71
However, patients with a high risk of bleeding (Child-Pugh
class B/C or endoscopic red color sign), are considered for
nonselective beta-blocker therapy.70 The dose of nonselec-
tive beta-blockers is adjusted for a reduction in the resting
heart rate by 25%, to 55 beats/minute, or until the occurrence
of side effects. In Koreans, the mean adjusted dose of
propranolol is 160 mg/day.72,73
3-3-3. Prevention of first bleeding in patients with large
In large esophageal varices, endoscopic variceal ligation
(EVL) and nonselective beta-blockers are effective in
preventing the first bleeding occurrence.74,75 In patients with
large varices (F2 or F3), which have never been observed to
bleed, nonselective beta-blockers or EVL is recommended.
Repeated EVL is recommended until the disappearance
of esophageal varices.76 Low doses of carvedilol have been
shown to lower the frequency of variceal bleeding
Ki Tae Suk, et al. Revision and update on clinical practice guideline for liver cirrhosis 7
3. How can a first variceal bleeding be prevented in patients
- In patients without varices, a nonselective beta-blockers
are not recommended for the purpose of preventing the
formation of varix and first bleeding of esophageal varix.
- Nonselective beta-blockers should be considered for
patients with small varices which have never bled but
have a high risk of bleeding (Child-Pugh class B/C or red
color sign on endoscopy). (B1)
- In patients with large varices (F2 or F3) in which bleeding
has never been observed, nonselective beta-blockers or
EVL are recommended. (A1)
4. How should nonselective beta-blockers be administered to
patients with LC?
- Nonselective beta-blockers are adjusted at the dose of
reduction in resting heart rate by 25% or 55 beats/minute,
or until the side effects occur. (B1)
5. How to prevent recurrence of variceal bleeding?
- Patients who experience acute variceal bleeding need
treatment to prevent rebleeding. (A1)
- EVL alone or in combination with nonselective
beta-blockers should be considered for the prevention of
- TIPS should be considered as a rescue therapy in Child-
Pugh A/B patients in whom other therapies have failed.
- Liver transplantation should be considered for patients
who meet indications for liver transplantation. (B1)
with lesser side effects as compared with EVL. However,
additional research is needed before they can be routinely
used.66,77 Combination therapy with EVL and nonselective
beta-blockers for the prevention of first bleeding has shown
no differences as compared with monotherapy.78
3-4. Prevention of variceal rebleeding
3-4-1. Definition and diagnosis
Variceal rebleeding is defined as bleeding after 5 days of
recovery from acute variceal bleeding.70 It is diagnosed
similar to acute variceal bleeding.
Nonselective beta-blockers alone or combination therapy
with isosorbide mononitrate are known to be effective in the
prevention of rebleeding.79 EVL shows better outcomes than
endoscopic injection sclerotherapy in endoscopic therapy
for prevention of rebleeding.80 Rebleeding has been reported
in 32% of patients after EVL. Combination therapy of EVL
and nonselective beta-blockers has been shown to have
better outcomes than EVL alone.81,82
TIPS shows a significantly low rebleeding rate as compared
with endoscopic therapy. However, it shows a significantly
high incidence of hepatic encephalopathy. TIPS is not
recommended as a first-line therapy for esophageal variceal
bleeding and is recommended only as a rescue therapy when
combination therapy fails.83 Liver transplantation should be
considered for patients who meet indications for liver
If the hepatic venous pressure gradient is reduced to less
than 12 mmHg or to more than 20% reduction in baseline
levels by medical therapy, the incidence rate of rebleeding is
low (10%).86 In such cases, further endoscopic therapy may
not be required.
3-5. Gastric varices
3-5-1. Definition and diagnosis
Gastric varices are enlarged submucosal veins of the
stomach that cause critical upper gastrointestinal bleeding.
Gastric varices occur in approximately 20% of patients with
portal hypertension, and the bleeding rate in 2 years is
known to be 25%.87 Diagnosis is performed by endoscopy.
Endoscopic ultrasound can also be helpful.88
Gastroesophageal varices are classified depending on
whether esophageal varices are extended along lesser
curvature (gastroesophageal varices, GOV1) or gastric
fundus (GOV2). Gastric varices alone are classified as
varices located in the fundus (isolated gastric varices, IGV1)
and any other regions, i.e., stomach or duodenum (IGV2).87
3-5-3. Treatment and prevention
EVL is recommended for the treatment of GOV1.
Endoscopic variceal obturation (EVO) can be an alter-
native.89-93 EVO involves the injection of tissue adhesives
such as N-butyl-2-cyanoacrylate (histoacrylⓇ) into the
varices via endoscopy and can be recommended in treating
GOV2 and IGV.91,94-96 Endoscopic injection sclerotherapy is
not recommended in treating GOV2 or IGV1 because of its
low rate of hemostasis, high rate of rebleeding, and other
complications.97-100 If endoscopic treatment is not possible,
8 The Korean Journal of Hepatology Vol. 18. No. 1, March 2012
6. How should gastric variceal bleeding be treated?
- In gastric variceal bleeding, EVL or EVO are considered
for GOV1 accompanying esophageal varices extended
along the lesser curvature. (B1)
- EVO is preferable in patients with GOV2 or IGV1. If
endoscopic treatment is not possible, TIPS can be used. If
gastric varix is accompanied with gastrorenal shunt,
balloon-occluded retrograde transvenous obliteration can
be considered. (B1)
- Surgery such as distal splenorenal shunt or vascular shunt
should be considered for patients (Child-Pugh A/B) and
liver transplantation for patients (Child-Pugh B/C) who
are not eligible for endoscopic treatment.
7. How should portal hypertensive gastropathy be treated?
- If chronic bleeding due to portal hypertensive gastropathy
presents, nonselective beta-blockers can be used. (B1)
1. How should ascites of LC be diagnosed?
- Paracentesis should be performed when Grade 2 or 3
ascites occurs, when there is clinical suspicion of
infection, or when there are complications of LC such as
encephalopathy or kidney dysfunction. (A1)
- When the initial paracentesis is performed, a total cell
count and differential, albumin, and total protein tests
should be performed. A culture of ascitic fluid in blood
culture bottles at the bedside is recommended. (A1)
- If serum-ascites albumin gradient is greater than or equal
to 1.1 g/dL, it indicates ascites by portal hypertension. (B1)
TIPS can be performed.101,102 If a gastrorenal shunt is
present, balloon-occluded retrograde transvenous obliteration
can be performed.103-106 Surgery, such as distal splenorenal
shunting or vascular shunting, can be attempted if endoscopic
treatment is not possible in case of Child-Pugh A/B patients,
while liver transplantation is considered in the case of
Child-Pugh B/C patients.107
Empirical use of nonselective beta-blockers, balloon-
occluded retrograde transvenous obliteration, and EVO can
prevent first gastric variceal bleeding, while EVO, TIPS,
and balloon-occluded retrograde transvenous obliteration
are considered to prevent gastric variceal rebleeding.70,108
3-6. Portal hypertensive gastropathy
Portal hypertensive gastropathy is diagnosed when gastric
mucosal changes of snake-skin appearance (or mosaic
pattern) are found on endoscopy in patients with portal
hypertension.109 When gastric mucosal changes alone are
found, this is diagnosed as a mild form. When red or dark
brown viscous changes with changes in gastric mucosa are
found, it is considered severe.72 Severe portal hypertensive
gastropathy causes more chronic bleeding than does the mild
In chronic bleeding due to portal hypertensive gastropathy,
the goal of treatment is lowering the portal pressure with
nonselective beta-blockers. In addition, iron supplementation
is recommended.111 Despite these treatments, if repeated
transfusions are needed for the treatment of chronic anemia,
TIPS can be considered.112
Ascites is the most common complication in LC,
occurring in 60% of the patients with compensated LC
within 10 years.113 Ascites appears in 2/3 of the patients who
required admission due to LC,114 and 60% of the patients
requiring paracentesis is because of LC.115
Abdominal ultrasound can diagnose ascites with only 100
mL.116 Ascites is classified by the amount of fluid as follows:
Grade 1 is diagnosed through imaging study, Grade 2
through inspection and physical examination, Grade 3 based
on marked abdominal expansion. Paracentesis is the most
useful and simple diagnostic tool in Grade 2 or 3 ascites.
Furthermore, paracentesis should be performed in cirrhotic
patients with fever, abdominal pain, bleeding, encephalopathy,
hypotension, or kidney dysfunction to assess for spontaneous
bacterial peritonitis (SBP), since 10-27% of the patients with
ascites have SBP.117 The main purpose of paracentesis is to
discriminate the cause of ascites. Therefore, screening tests
should include total cell count and differential, albumin, and
total protein. Blood cell count is the most useful test for
diagnosing SBP. For differential diagnosis of ascites, a
serum-ascites albumin gradient can be calculated. If the
serum-ascites albumin gradient is is greater than of equal to
1.1 g/dL, ascites is ascribed to portal hypertension with an
accuracy of 97%.
Ki Tae Suk, et al. Revision and update on clinical practice guideline for liver cirrhosis 9
Table 3. Treatment of ascites depending on the grade
Grade 1, mild Grade 2, moderate Grade 3, severe
Large volume paracentesis●
Grade 1, a small amount of ascites detected in the ultrasound test; Grade 2, ascites of the amount which distends abdomen
symmetrically; Grade 3, ascites of the large volume which distends abdomen; ●, major treatment; ○, recommended.
Although controversial,118 a low salt diet is considered
effective for controlling ascites and shortening hospitalization.
Less than 5 g/day of salt (sodium for 2 g, 88 mEq) is
recommended. When plasma sodium is lower than 120-125
mEq/L, water intake should be restricted to 1-1.5 L/day.119
If severe ascites is present, diuretic therapy should be used
for negative sodium balance.120,121 Secondary hyperaldo-
steronism in patients with LC induces reabsorption of
sodium and water in the distal renal tubule and collecting
tubule, consequently causing hypokalemia. Aldosterone
antagonists inhibit this mechanism, and hence is mainly
used for controlling ascites in patients with LC. Spirono-
lactone has a long half-life but has a slow onset of action,
and therefore requires 3-4 days to achieve a stable
concentration. It is initiated at a dose of 50-100 mg/day, with
a maximum dose of 400 mg/day. Side effects include
hyperkalemia, gynecomastia, mastalgia, hyposexuality, and
Loop diuretics operate by blocking Na-K-2Cl receptors in
the thick ascending limb of Henle’s loop. They are mostly
used along with aldosterone antagonists in patients with LC.
Hypokalemia may occur as a side effect, but via such
mechanism, hyperkalemia caused by the aldosterone anta-
gonist can be corrected. The starting dose is 20-40 mg/day,
with the maximum dose being 160 mg/day. Monotherapy
with loop diuretics is less effective than aldosterone anta-
gonist monotherapy. Spironolactone monotherapy can be
used initially on patients with ascites.123 Combination
therapy of an aldosterone antagonist and a loop diuretic is
recommended at first in a ratio of 100:40, which stabilizes
plasma potassium levels. Combination therapy shows a
faster effect in controlling ascites and lowers the possibility
of hyperkalemia as compared to aldosterone monotherapy.124
When peripheral edema is present, the rate of weight loss
should be no greater than 1 kg/day. For patients without
edema, 0.5 kg/day of weight loss is ideal.120,125 If there is no
weight loss even with 5 g/day of salt intake, the diet and
diuretic dose should be evaluated by examining the amount
of urinary sodium excretion per day.120,126 Patients with low
salt intake should not excrete more than 78 mEq of urinal
sodium in 24 hours. In such patients, if urinary sodium
excretion is more than 78 mEq, low salt intake is judged not
to be followed. When the excretion is less than 78 mEq, the
diuretic is considered to be inadequate and the dose needs
to be increased. Spot urine Na/K ratio of more than 1 repre-
sents 24 hours urine sodium excretion more than 78 mEq.127
It is important to check the weight loss, vital sign, changes
in consciousness level, and the level of plasma sodium,
potassium, and creatinine during diuretic administration.
When plasma sodium is more than 126 mEq/L, diuretics can
be used without the restriction of water intake. However,
when plasma sodium is less than 125 mEq/L, the physician
should consider cessation or reduction in the dose of the
diuretic and restriction of water intake. If plasma sodium is
less than 120 mEq/L, the diuretic and water intake should be
stopped and a plasma expander such as albumin should be
administered. If plasma sodium is less than 125 mEq/L with
kidney dysfunction, the diuretic should be stopped and a
plasma expander should be administered.128 If plasma
potassium is less than 3.5 mEq/L, the dose of loop diuretic
should be reduced or stopped. If plasma potassium is more
than 5.5 mEq/L, the dose of aldosterone antagonist should
be reduced. And if plasma potassium is more than 6.0
mEq/L, the aldosterone antagonist should be ceased.120
4-2-2. Therapeutic paracentesis (reference to intractable
Therapeutic paracentesis is an effective treatment for
tension-type ascites, because it relieves the symptoms more
quickly than diuretics and shortens hospitalization
10 The Korean Journal of Hepatology Vol. 18. No. 1, March 2012
2. How should ascites of LC be treated?
- Patients with cirrhotic ascites should be advised to take in
less than 5 g of salt a day. (B1)
- When the serum sodium is normal, restriction of water
intake is not necessary. (B1)
- Bed rest is not recommended for the treatment of ascites.
- The first-choice diuretic for patients with cirrhotic ascites
is aldosterone antagonist. (A1) Loop diuretics can be used
along with aldosterone antagonist. (B1) Spironolactone
can be used with a starting dose of 50-100 mg/day up to
400 mg/day. To increase the diuretic effects and maintain
a normal serum potassium level, 20-40 mg of furosemide
should be used with spironolactone (40:100) beginning at
the initial stage.
- When peripheral edema is present, the rate of weight loss
should be recommended up to 1 kg/day. For patients
without edema, 0.5 kg/day of weight loss should be
- In cases of severe hyponatremia, kidney dysfunction,
encephalopathy, or severe muscle spasms, diuretics should
be stopped. (B1)
- In cases of hypokalemia, loop diuretic should be reduced
or stopped, and if hyperkalemia occurs, the dose of
aldosterone antagonist should be adjusted. (B1)
- Therapeutic large volume paracentesis is recommended as
the first-line treatment for tension-type ascites. (A1)
Table 4. Definition and diagnosis of refractory ascites206
Diuretic resistant ascites Being not responsive to sodium limit and diuretic, ascites is not controlled, and recurs early
Diuretic intractable ascites Since sufficient amount of diuretic cannot be given for its complication, ascites is not controlled, and
Treatment period For over a week, give sufficient amount of diuretics (spironolactone 400 mg/day and furosemide 160
mg/day) and restriction of sodium intake to 5 g/day
Treatment responseBody weight loss is less than 800 g during 4 days, and the amount of urine sodium excretion is less
than the amount taken
Early recurrence of ascite Within 4 weeks after paracentesis, grade 2 or 3 ascites recurs
Complications Hepatic encephalopathy
Renal dysfunction: after giving diuretics, serum creatinine goes up over 100%, and exceeds 2.0 mg/dL
Hyponatremia: serum sodium reduces by over 10 mEq/L, and goes down below 125 mEq/L
Hypokalemia or hyperkalemia: serum potassium goes down below 3 mEq/L, or goes up beyond 6 mEq/L
4-3. Refractory ascites and hyponatremia
4-3-1. Refractory ascites
Refractory ascites130 is defined as fluid overload that (1) is
not controlled despite restriction of sodium intake and the
maximum dose of diuretics, and (2) recurs rapidly after
paracentesis. There are 2 types of refractory ascites-diuretic
resistant and diuretic intractable (Table 4).
Large-volume paracentesis is not considered for every
patient as a first-line treatment. It can be selectively
performed in occasions in which the patient has difficulties
eating or breathing because of abdominal distension. After
relieving the symptoms by paracentesis, the maintenance
treatment should be administered. In the case of large-
volume paracentesis over 5 L, an infusion of 8-10 g of
albumin per L is recommended. In the case of paracentesis
less than 5 L, although the occurrence of circulatory
dysfunction is not frequent, an infusion of volume expander
can be considered. Albumin can also be used for this
purpose.125,131 Medications such as midodrine,132 norad-
renaline,133 or terlipressin134 can be used. Compared with
repetitive paracenteses, TIPS is an effective method to
prevent the recurrence of ascites and the occurrence
hepatorenal syndrome. However, hepatic encephalopathy
occurs in 30-50% of cases after TIPS. As 21% of the patients
with refractory ascites die within 6 months and the median
survival period is also less than 1 year, they should be
considered for liver transplantation.135
The diagnostic criterion for hyponatremia is less than 130
mEq/L.119 A hypervolemic state can be corrected to normal
by a negative water balance. Eventually, dilutional
hyponatremia can be improved.136 Restriction of water
intake can prevent a decrease in the serum sodium level.125
Hypertonic sodium injection can worsen ascites and
edema.137 Plasma expanders can be useful in the treatment of
hyponatremia.138 Vaptan,139 a selective vasopressin 2 receptor
antagonist of arginine vasopressin, leads to the excretion of
Ki Tae Suk, et al. Revision and update on clinical practice guideline for liver cirrhosis 11
3. How should intractable ascites be treated?
- Repetitive large volume paracentesis is recommended in
patients with refractory ascites. (A1)
- In the case of large volume paracentesis, 8-10 g/L (albumin/
ascites) is recommended for the prevention of postparacentesis
circulation dysfunction. (A1)
- TIPS can be used for the treatment of refractory ascites. (B1)
- Because of poor prognosis, liver transplantation is
recommended in patients with refractory ascites. (A1)
- If the serum sodium concentration is less than 120-125
mEq/L, restriction of fluid intake to 1-1.5 L/day is recom-
- Albumin or vaptan can be used in severe dilutional hypo-
natremia (<125 mEq/L). (B2)
Table 5. New International Ascites Club's diagnostic criteria of hepatorenal syndrome
1) Cirrhosis with ascites
2) Serum creatinine >133 mmol/L (1.5 mg/dL)
3) No improvement of serum creatinine (decrease to a level of 133 mmol/L) after at least 2 days with diuretic withdrawal and volume
expansion with albumin; the recommended dose of albumin is 1 g/kg of body weight per day up to a maximum of 100 g/day
4) Absence of shock
5) No current or recent treatment with nephrotoxic drugs
6) Absence of parenchymal kidney disease as indicated by proteinuria >500 mg/day, microhematuria (>50 red blood cells/high-power
field), and/or abnormal renal ultrasound.
solute-free water. This agent can be used in the treatment of
hyponatremia caused by inappropriate antidiuretic hormone
secretion, heart failure, or liver cirrhosis. In the United
States and Europe, tolvaptan and conivaptan are approved
for the treatment of severe hyponatremia (<125 mEq/L).
4-4. Hepatorenal syndrome
4-4-1. Definition and diagnosis
Renal failure in LC occurs in 2 forms. First, type 1
hepatorenal syndrome is a rapid progressive acute renal
dysfunction which occurs due to the strong contraction of
the renal vasculature. Type 2 hepatorenal syndrome is a
relatively slow process with a rather moderate renal
dysfunction. The most important mechanism involved in the
occurrence of hepatorenal syndrome is decreased effective
blood volume due to the dilation of the splanchnic and
peripheral circulation. This situation activates the sympathetic
nervous system as well as the renin-angiotensin system and
causes functional renal disorder.140-142
In 1994, the International Ascites Club announced the
diagnostic criteria for hepatorenal syndrome; in 2007,
they revised these criteria to providing clearer diagnostic
methods and including infectious diseases (Table 5).130,143
Dilatation of splanchnic artery and decrease in effective
arterial blood volume arethe primary mechanisms of
hepatorenal syndrome. The effect of albumin monotherapy
is not sufficient in this situation.144,145 Vasoconstrictors have
been used in the treatment of the hepatorenal syndrome, and
combination therapy with vasoconstrictors and albumin is
effective in hepatorenal syndrome. The combination therapy
of terlipressin and albumin improves renal function in
60-75% of the patients.144,146-152 Maintenance therapy is
possible up to 15 days or until the serum creatinine
levels decrease (<1.5 mg/dL). Further, long-term usage
(approximately 2 months) can be considered as a bridging
therapy prior to liver transplantation.153,154 The combination
therapy of noradrenaline and albumin can also improve
renal function in hepatorenal syndrome.155,156 Combination
therapy of midodrine and octreotide or triple therapy of
midodrine, octreotide, and albumin also meaningfully improve
renal function in patients with hepatorenal syndrome.157-160
After administration of terlipressin, hepatic venous
pressure gradient is known to decrease while the renal blood
flow increases.161,162 Therefore, it can also be used for
treatment in patients with secondary renal insufficiency due
to variceal bleeding.147,163,164
Although TIPS157,165,166 reduces the serum creatinine
levels in most patients with hepatorenal syndrome, the effect
is slower than the combined use of terlipressin and albumin.
In a group that used molecular adsorbent recirculating
system167 in the treatment of hepatorenal syndrome,
laboratory findings (serum creatinine, bilirubin, and
prothrombin time) and 30-days survival rate were improved
compared to the group that underwent intermittent dialysis
and drug therapy. Continuous arterio-venous hemofiltration
and continuous veno-venous hemofiltration can be considered
to minimize the changes in blood pressure.168,169
12 The Korean Journal of Hepatology Vol. 18. No. 1, March 2012
4. How should hepatorenal syndrome be treated?
- In type 1 hepatorenal syndrome, combination therapy of
terlipressin and albumin can improve renal function. (A1)
- In type 1 hepatorenal syndrome, combination therapy of
midodrine, octreotide, and albumin can be considered.
- The best treatment for type 1 hepatorenal syndrome is
liver transplantation. (A1)
- In high risk patients who have ascites accompanied by
SBP, the use of albumin can decrease the incidence of
hepatorenal syndrome. (A1)
5. How should SBP be diagnosed and treated?
- If SBP is suspected and the result of paracentesis show a
PMN of more than 250/mm3, empirical antibiotic therapy
should be started immediately without results of ascitic
fluid culture. (A1)
- Third-generation cephalosporine is recommended as an
initial antibiotic. (A1)
- The patient with symptoms or signs of infection should
receive empirical antibiotics while awaiting of ascitic fluid
culture even if the number of PMN is less than 250/mm3.
- If the secondary bactrieal peritonitisis suspected, an
imaging study such as a CT should be performed (A1),
and additional examinations such as those for total
protein, LDH, glucose, or gram staining can be performed.
- If the patient has a history of SBP, gastrointestinal bleeding,
or protein in ascites less than 1.5 g/dL, although there is no
gastrointestinal bleeding, prophylactic antibiotics should
be considered because the chance of SBP is high. (B1)
Hepatorenal syndrome can be prevented by inhibiting the
decrease of plasma volume. Diuretics and lactulose should
be used carefully to prevent excessive fluid loss.132,133,170,171
In patients with SBP, the use of albumin and antibiotics
reduce the incidence of hepatorenal syndrome.172,173 The use
of oral norfloxacin has been shown to reduce the occurrence
of hepatorenal syndrome and increase 3-month survival
rates in patients with low serum protein (<1.5 g/dL) or renal
insufficiency (creatinine ≥1.2 mg/dL, or blood urea nitrogen
≥25 mg/dL, or serum Na ≤130 mEq/L).174 Administration of
pentoxifylline improved survival rates as compared to
corticosteroids in severe acute alcoholic hepatitis patients
(Maddrey’s discriminant factor ≥32).175-177
4-5. Spontaneous bacterial peritonitis
4-5-1. Definition and diagnosis
SBP is bacterial infection of ascites, without an evident
intra-abdominal, surgically treatable source of infection. It
occurs in 10-30% of the patients with cirrhotic ascites and
recurs in 70% of the patients within 1 year even if
SBP can be diagnosed in patients with findings of ascitic
polymorphonuclear leukocyte (PMN) ≥250/mm3and bacteria
in the ascitic culture without an evident intra-abdominal
infection. If ascites fluid contains red blood cells, PMN is
calculated by subtracting 1/mm3 per red blood cell 750
/mm3. Culture-negative neutrocytic ascites is a condition
where ascitic PMN ≥250/mm3 but no cultured bacteria are
observed. These patients show a clinical course mostly
similar to patients with SBP. Empiric antibiotics treatment is
recommended. Monomicrobial non-neutrocytic bacterascites
is a condition with ascitic PMN <250/mm3, but cultured
single-strain bacteria being observed.
Administration of third generation cephalosporin is
recommended. Cefotaxime is recommended at a dose of 2 g
every 6-8 hours by intravenous injection. Subsequently,
selective antibiotic therapy based on the result of ascites
culture should be administered for 5-10 days.179 Treatment
duration varies according to the symptoms and/or results of
antibiotic sensitivity. Albumin during the treatment of SBP,
especially in patients with renal dysfunction, can be
If a patient presentsacute gastrointestinal bleeding,
administration of norfloxacin at a dose of 400 mg twice daily
for 7 days orally or ceftriaxone at a dose of 1 g daily for
7 days intravenously is effective in preventing SBP. In
patients with a concentration of protein in ascites fluid less
than 1.5 g/dL or bilirubin in plasma is more than 2.5 mg/dL,
administration of norfloxacin at a dose of 400 mg daily for
longer than 6 months orally is effective in prolonging the
5. Hepatic encephalopathy
Hepatic encephalopathy is a neuropsychiatric syndrome
that follows liver dysfunction. Patients with hepatic
encephalopathy can show various neurological illnesses
Ki Tae Suk, et al. Revision and update on clinical practice guideline for liver cirrhosis 13
Table 6. Classification of hepatic encephalopathy180
HE type NomenclatureSubcategorySubdivisions
A Encephalopathy associated with acute liver failure
B Encephalopathy associated with portal-systemic bypass and no intrinsic
C Encepahlopathy associated with cirrhosis and portal hypertension/or
Episodic HE Precipitated
HE, hepatic encephalopathy.
Table 7. West-Haven criteria for hepatic encephalopathy183
Grade ConsciousnessIntellect and behaviorNeurologic findings
0 Normal Normal Normal examination; if impaired psychomotor
testing then MHE
1 Mild lack of awareness Shortened attention span; impaired
addition or subtraction
Mild asterixis or tremor
2 Lethargic Disoriented; inappropriate behavior Obvious asterixis; slurred speech
3 Somnolent but arousable Gross disorientation; bizarre behaviorMuscular rigidity and clonus; hyperreflexia
4 ComaComa Decerebrate posturing
MHE, minimal hepatic encephalopathy.
such as cognition and orientation disorders. Hepatic
encephalopathy is classified into 3 groups according to the
causative liver disease (Table 6).180,181
Hepatic encephalopathy is generally accompanied by
advanced liver disease; therefore, muscle weakness, jaundice,
ascites, palmar erythema, edema, spider telangiectasias, and
fetor hepaticus can be noted on physical examination.
Clinicians should check for gastrointestinal hemorrhage,
uremia, use of anti-psychotics or diuretics, protein hyper-
ingestion, infection, constipation, dehydration, electrolyte
imbalance, etc.182 Common symptoms include concentration
disorders, sleep disorders, and movement disorders, including
lethargy or coma. The severity of hepatic encephalopathy
can be evaluated using the West Haven criteria (Table 7).183
Venous levels of ammonia are not helpful because they
are not proportional to the severity of hepatic encephalopathy
and some patients with sever hepatic encephalopathy have
normal venous ammonia levels.184
Brain MRI is considered better than brain CT in the
diagnosis of brain edema accompanying hepatic failure, but
this is not true for hepatic encephalopathy. Brain CT is
useful when differentiating between organic causes of
neuropsychiatric disorders such as intracranial hemorrhage.185
The goal of treatment is to prevent secondary damage
caused by decreased consciousness, normalize the patient’s
state of consciousness, prevent recurrence, and to improve
the prognosis and quality of life by eliminating the social
and economic restrictions caused by hepatic encephalopathy.
The precipitating factor can be identified in more than 80%
of patients with hepatic encephalopathy.182 The currently
known precipitating factors of hepatic encephalopathy
and the corresponding tests and treatments are shown in
14 The Korean Journal of Hepatology Vol. 18. No. 1, March 2012
Table 8. Precipitating factors, tests, and treatment of hepatic encephalopathy186
Gastrointestinal bleeding Endoscopy, complete blood count, digital rectal
examination, stool blood test
Transfusion, bleeding treatment, vasoactive drugs
Infection Complete blood count, chest x-ray, urine analysis,
culture, diagnostic paracentesis
ConstipationHistory taking, abdomen x-ray Enema or drug therapy
Protein intake History takingLimiting protein intake
Dehydration Skin elasticity, blood pressure, pulse rate, blood
urea nitrogen, creatinine
Stop diuretics or reduction, fluid therapy
Renal dysfunction Blood urea nitrogen, creatinineStop diuretics or reduction, albumin, fluid therapy
Hyponatremia Serum sodium concentration Restriction water consumption, diuretics dose
adjustment or stop
Hypokalemia Serum potassium concentration Diuretics dose adjustment or stop
BenzodiazepinesHistory taking Stop drug, flumazenil
Acute liver dysfunctionLiver function test Conservative treatment
The primary treatment of hepatic encephalopathy is
nonabsorbable disaccharides such as lactulose (β-galactosido-
fructose) or lactitiol (β-galctoside sorbitol). These
treatments lead to the recovery of 70-90% of patients with
hepatic encephalopathy. Although nonabsorbable disaccha-
rides have been reported to have no significant effect on
hepatic encephalopathy,187 randomized controlled studies
have indicated a positive effect of lactulose in the treatment
and prevention of hepatic encephalopathy.188,189 Enema with
nonabsorbable disaccharides can be used until the cons-
ciousness is recovered. After consciousness is restored,
nonabsorbable disaccharides (15-45 mL, orally 2-4 times/day)
should be recommended for loose stool defecation 2-3 times
Antibiotics such as neomycin, metronidazole, and
rifaximin that are not absorbed by the intestine, affect
urea-producing bacteria and reduce the generation of
ammonia, thereby improving hepatic encephalopathy.
Neomycin and metronidazole are not recommended as
atreatment of hepatic encephalopathy because of their side
effects such as intestinal malabsorption, nephrotoxicity, and
ototoxicity for neomycin and peripheral neuropathy for
metronidazole.190 Rifaximin maintains high levels of
concentration in the intestine because it is not absorbed by
the intestine and remains in an active form until it is
excreted. It has a broad antimicrobial activity on aerobic and
anaerobic gram-positive and gram-negative bacteria. It has
been proven effective and safe in hepatic encephalopathy,191-193
and recently has been focused upon as a first-line treatment
for hepatic encephalopathy with a maximum dose of 1,200
Ornithine and aspartate are important substrates used to
metabolize ammonia to urea and glutamine. L-ornithine-
L-aspartate (LOLA) can therefore be administered to
patients with hepatic encephalopathy for reducing blood
ammonia levels, with subsequent improvements in hepatic
encephalopathy. LOLA is available in oral and injection
forms, both of which are available in Korea currently.
5-3-2. Liver transplantation
Liver transplantation is indicated in patients with severe
hepatic encephalopathy, who do not respond to the above
treatments. Patient with acute liver failure who shows hepatic
encephalopathy are also considered for liver transplantation
because of the poor prognosis.194
5-3-3. Prevention of relapse
Because the recurrence rate of hepatic encephalopathy is
50-70%,189,195,196 therapy for the prevention of recurrence
should be considered. Lactulose189 or rifaximin196 have been
used for the prevention of recurrence.
5-4. Minimal hepatic encephalopathy
5-4-1. Definition and diagnosis
Minimal hepatic encephalopathy is a mild form of hepatic
encephalopathy that is defined as a cognitive dysfunction
presenting a abnormal psychometric tests without clinical
Ki Tae Suk, et al. Revision and update on clinical practice guideline for liver cirrhosis 15
1. What are the precipitating factors of hepatic
- Precipitating factors of hepatic encephalopathy are
gastrointestinal bleeding, infection, constipation, excessive
intake of protein, dehydration, renal function disorder,
electrolyte imbalance, psychoactive medication, and acute
hepatic injury. (A1)
2. How should hepatic encephalopathy be treated?
- Nonabsorbent disaccharides (ex. lactulose, lactitol) (A1)
and rifaximin (B1) are recommended for treating patients
with hepatic encephalopathy. Nonabsorbable disaccharides
can be used to adjust the bowel movement-loose stool
(2-3 times/day), and rifaximin 1,200 mg should be given
orally in 2-3 divided doses for 1-3 weeks.
- A lactulose enema is recommended in severe hepatic
encephalopathy (West Haven grade ≥III). (A1)
- LOLA can be used in patients with hepatic
encephalopathy, and LOLA of 20 g can be injected daily
for 1-2 weeks or LOLA of 6 g can be given orally 3 times
per day for 1-2 weeks. (B2)
- Flumazenil can be used in patients with hepatic
encephalopathy caused by benzodiazepine for the
improvement of consciousness. (B2)
- In patients who do not respond to treatment or acute liver
injury with hepatic encephalopathy, liver transplantation is
- In patients with a history of hepatic encephalopathy,
nonabsorbable disaccharide can be used until patients have
loose stools 2-3 times a day (A1), or 600 mg of rifaximin
can be used twice a day (B1).
3. How protein be supplied to patients with hepatic encephal-
- Protein intake should be restricted in patients with initial
hepatic encephalopathy, and gradually can be increased
according to the patient’s condition. (B1)
- Oral branched-chain amino acids can be used as a protein
source in case of worsening or recurrence of hepatic
encephalopathy due to as a consequence of high protein
4. Is it necessary to examine and treat minimal hepatic
encephalopathy for patients with LC?
- In patients with LC, if there are any symptoms of low
cognitive function, tests and treatment for minimal hepatic
encephalopathy can be considered. (B1)
symptoms.180 Overall, 22-74% of patients with non-fulminant
hepatic encephalopathy have minimal hepatic encephalo-
pathy,197 and its frequency is proportional to patient age and
severity of liver disease.197 It is impossible to diagnose
minimal hepatic encephalopathy on clinical examination
alone. Only mild disturbances in cognitive and psychomotor
functions can be observed. Patients with minimal hepatic
encephalopathy exhibit disability in most functional
behaviors such as social connection, alertness, emotional
behavior, sleep, work, and leisure.188,198
Mini-Mental State Examination can be useful in differen-
tiating West Haven criteria 0 and stage 1-2, and if the score is
23 or lower, it suggests that the patient has overt hepatic
encephalopathy causing a cognitive disorder and is not
a primary target for psychometric tests.199 Since there are
still no decisive diagnostic tests, psychometric hepatic
encephalopathy score battery is recommended as a standard
method consisting of number connection test-A, number
connection test-B, line drawing test, serial dotting test, and
digit symbol test, and its benefits have been proven in
studies from Spain, Germany, India, and Korea.181,200-202
Cognition and health-related quality of life improve
significantly in the treatment group compared to placebo
group.188 It has been reported that microviral agents (e.g.,
probiotics, synbiotics, etc.) improve minimal encephalopathy
by changing intestinal normal flora and suppressing the
production of ammonia.203 Even though reports are
displayed that LOLA204 and acetyl L-carnitine205 improved
minimal encephalopathy, there is no evidence regarding its
This research was supported by a grant from the Ministry
of Health and Welfare, Republic of Korea (A102065) and
the Korean Association for the Study of the Liver (KASL).
The Korean version of this guideline is available on the
KASL web site (http://www.kasl.org/). This version is revision
and update of the clinical practice guideline established by
the Korean Association for the Study of the Liver (KASL) in
Conflict of interest
Authors attest that there are no commercial associations
that might be a conflict of interest in relation to the sub-
16 The Korean Journal of Hepatology Vol. 18. No. 1, March 2012
1. Lee HS, Kim JK, Cheong JY, Han EJ, An SY, Song JH, et al. Prediction
of compensated liver cirrhosis by ultrasonography and routine blood
tests in patients with chronic viral hepatitis. Korean J Hepatol
2. Aubé C, Oberti F, Korali N, Namour MA, Loisel D, Tanguy JY, et al.
Ultrasonographic diagnosis of hepatic fibrosis or cirrhosis. J Hepatol
3. Colli A, Fraquelli M, Andreoletti M, Marino B, Zuccoli E, Conte D.
Severe liver fibrosis or cirrhosis: accuracy of US for detection--analysis
of 300 cases. Radiology 2003;227:89-94.
4. Gaiani S, Gramantieri L, Venturoli N, Piscaglia F, Siringo S, D'Errico A,
et al. What is the criterion for differentiating chronic hepatitis from
compensated cirrhosis? A prospective study comparing ultrasonography
and percutaneous liver biopsy. J Hepatol 1997;27:979-985.
5. Hung CH, Lu SN, Wang JH, Lee CM, Chen TM, Tung HD, et al.
Correlation between ultrasonographic and pathologic diagnoses of
hepatitis B and C virus-related cirrhosis. J Gastroenterol 2003;38:
6. Kudo M, Zheng RQ, Kim SR, Okabe Y, Osaki Y, Iijima H, et al.
Diagnostic accuracy of imaging for liver cirrhosis compared to
histologically proven liver cirrhosis. A multicenter collaborative study.
Intervirology 2008;51(Suppl 1):17-26.
7. Di Lelio A, Cestari C, Lomazzi A, Beretta L. Cirrhosis: diagnosis with
sonographic study of the liver surface. Radiology 1989;172:389-392.
8. Baik SK, Kim JW, Kim HS, Kwon SO, Kim YJ, Park JW, et al. Recent
variceal bleeding: Doppler US hepatic vein waveform in assessment of
severity of portal hypertension and vasoactive drug response. Radiology
9. Harbin WP, Robert NJ, Ferrucci JT Jr. Diagnosis of cirrhosis based on
regional changes in hepatic morphology: a radiological and pathological
analysis. Radiology 1980;135:273-283.
10. Awaya H, Mitchell DG, Kamishima T, Holland G, Ito K, Matsumoto T.
Cirrhosis: modified caudate-right lobe ratio. Radiology 2002;224:
11. Park YN, Kim HG, Chon CY, Park JB, Sohn JH, Yang SH, et al.
Histological grading and staging of chronic hepatitis. Korean J Pathol
12. Rockey DC, Bissell DM. Noninvasive measures of liver fibrosis.
Hepatology 2006;43(Suppl 1):S113-S120.
13. Friedman SL. Molecular regulation of hepatic fibrosis, an integrated
cellular response to tissue injury. J Biol Chem 2000;275:2247-2250.
14. Bataller R, Brenner DA. Liver fibrosis. J Clin Invest 2005;115:209-218.
15. Dienstag JL, Goldin RD, Heathcote EJ, Hann HW, Woessner M,
Stephenson SL, et al. Histological outcome during long-term lamivudine
therapy. Gastroenterology 2003;124:105-117.
16. Yokosuka O, Takaguchi K, Fujioka S, Shindo M, Chayama K, Kobashi
H, et al. Long-term use of entecavir in nucleoside-naïve Japanese
patients with chronic hepatitis B infection. J Hepatol 2010;52:791-799.
17. Marcellin P, Chang TT, Lim SG, Sievert W, Tong M, Arterburn S, et al.
Long-term efficacy and safety of adefovir dipivoxil for the treatment of
hepatitis B e antigen-positive chronic hepatitis B. Hepatology 2008;48:
18. Schiff E, Simsek H, Lee WM, Chao YC, Sette H Jr, Janssen HL, et al.
Efficacy and safety of entecavir in patients with chronic hepatitis B and
advanced hepatic fibrosis or cirrhosis. Am J Gastroenterol 2008;103:
19. Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, Chang TT, Kitis G,
Rizzetto M, et al. Long-term therapy with adefovir dipivoxil for
HBeAg-negative chronic hepatitis B for up to 5 years. Gastroenterology
20. Poynard T, Massard J, Rudler M, Varaud A, Lebray P, Moussalli J, et al.
Impact of interferon-alpha treatment on liver fibrosis in patients with
chronic hepatitis B: an overview of published trials. Gastroenterol Clin
21. Bourlière M, Kahloun A, Gascou-Tessonnier G. Analogs and fibrosis
regression in hepatitis B. Gastroenterol Clin Biol 2009;33:923-929.
22. Chang TT, Gish RG, de Man R, Gadano A, Sollano J, Chao YC, et al. A
comparison of entecavir and lamivudine for HBeAg-positive chronic
hepatitis B. N Engl J Med 2006;354:1001-1010.
23. Lai CL, Shouval D, Lok AS, Chang TT, Cheinquer H, Goodman Z, et al.
Entecavir versus lamivudine for patients with HBeAg-negative chronic
hepatitis B. N Engl J Med 2006;354:1011-1020.
24. Marcellin P, Heathcote EJ, Buti M, Gane E, de Man RA, Krastev Z, et al.
Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic
hepatitis B. N Engl J Med 2008;359:2442-2455.
25. Buster EH, Hansen BE, Buti M, Delwaide J, Niederau C, Michielsen PP,
et al. Peginterferon alpha-2b is safe and effective in HBeAg-positive
chronic hepatitis B patients with advanced fibrosis. Hepatology 2007;
26. Liaw YF, Sung JJ, Chow WC, Farrell G, Lee CZ, Yuen H, et al.
Lamivudine for patients with chronic hepatitis B and advanced liver
disease. N Engl J Med 2004;351:1521-1531.
27. Chang TT, Liaw YF, Wu SS, Schiff E, Han KH, Lai CL, et al. Long-term
entecavir therapy results in the reversal of fibrosis/cirrhosis and
continued histological improvement in patients with chronic hepatitis
B. Hepatology 2010;52:886-893.
28. Lai CL, Gane E, Liaw YF, Hsu CW, Thongsawat S, Wang Y, et al.
Telbivudine versus lamivudine in patients with chronic hepatitis B. N
Engl J Med 2007;357:2576-2588.
29. Shiffman ML, Hofmann CM, Contos MJ, Luketic VA, Sanyal AJ,
Sterling RK, et al. A randomized, controlled trial of maintenance
interferon therapy for patients with chronic hepatitis C virus and
persistent viremia. Gastroenterology 1999;117:1164-1172.
30. Arase Y, Ikeda K, Suzuki F, Suzuki Y, Kobayashi M, Akuta N, et al.
Prolonged-interferon therapy reduces hepatocarcinogenesis in aged-
patients with chronic hepatitis C. J Med Virol 2007;79:1095-1102.
31. Nomura H, Kashiwagi Y, Hirano R, Tanimoto H, Tsutsumi N, Higashi
M, et al. Efficacy of low dose long-term interferon monotherapy in aged
patients with chronic hepatitis C genotype 1 and its relation to alpha-
fetoprotein: A pilot study. Hepatol Res 2007;37:490-497.
32. Saito Y, Saito H, Tada S, Nakamoto N, Horikawa H, Kurita S, et al.
Effect of long-term interferon therapy for refractory chronic hepatitis c:
preventive effect on hepatocarcinogenesis. Hepatogastroenterology
33. Akuta N, Suzuki F, Kawamura Y, Yatsuji H, Sezaki H, Suzuki Y, et al.
Efficacy of low-dose intermittent interferon-alpha monotherapy in
patients infected with hepatitis C virus genotype 1b who were predicted
or failed to respond to pegylated interferon plus ribavirin combination
therapy. J Med Virol 2008;80:1363-1369.
34. Di Bisceglie AM, Shiffman ML, Everson GT, Lindsay KL, Everhart JE,
Wright EC, et al. Prolonged therapy of advanced chronic hepatitis C
with low-dose peginterferon. N Engl J Med 2008;359:2429-2441.
35. Veldt BJ, Lainé F, Guillygomarc'h A, Lauvin L, Boudjema K, Messner
M, et al. Indication of liver transplantation in severe alcoholic liver
cirrhosis: quantitative evaluation and optimal timing. J Hepatol
36. Rafiq N, Younossi ZM. Effects of weight loss on nonalcoholic fatty
liver disease. Semin Liver Dis 2008;28:427-433.
37. Kim HK, Park JY, Lee KU, Lee GE, Jeon SH, Kim JH, et al. Effect of
body weight and lifestyle changes on long-term course of nonalcoholic
fatty liver disease in Koreans. Am J Med Sci 2009;337:98-102.
Ki Tae Suk, et al. Revision and update on clinical practice guideline for liver cirrhosis 17
38. St George A, Bauman A, Johnston A, Farrell G, Chey T, George J.
Independent effects of physical activity in patients with nonalcoholic
fatty liver disease. Hepatology 2009;50:68-76.
39. Johnson NA, Sachinwalla T, Walton DW, Smith K, Armstrong A,
Thompson MW, et al. Aerobic exercise training reduces hepatic and
visceral lipids in obese individuals without weight loss. Hepatology
40. Socha P, Horvath A, Vajro P, Dziechciarz P, Dhawan A, Szajewska H.
Pharmacological interventions for nonalcoholic fatty liver disease in
adults and in children: a systematic review. J Pediatr Gastroenterol Nutr
41. Belfort R, Harrison SA, Brown K, Darland C, Finch J, Hardies J, et al. A
placebo-controlled trial of pioglitazone in subjects with nonalcoholic
steatohepatitis. N Engl J Med 2006;355:2297-2307.
42. Aithal GP, Thomas JA, Kaye PV, Lawson A, Ryder SD, Spendlove I, et
al. Randomized, placebo-controlledtrial of pioglitazone in nondiabetic
subjects with nonalcoholic steatohepatitis. Gastroenterology 2008;135:
43. Neuschwander-Tetri BA, Brunt EM, Wehmeier KR, Oliver D, Bacon
BR. Improved nonalcoholic steatohepatitis after 48 weeks of treatment
with the PPAR-gamma ligand rosiglitazone. Hepatology 2003;38:
44. Sanyal AJ, Chalasani N, Kowdley KV, McCullough A, Diehl AM, Bass
NM, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic
steatohepatitis. N Engl J Med 2010;362:1675-1685.
45. Sanyal AJ, Mofrad PS, Contos MJ, Sargeant C, Luketic VA, Sterling
RK, et al. A pilot study of vitamin E versus vitamin E and pioglitazone
for the treatment of nonalcoholic steatohepatitis. Clin Gastroenterol
46. Harrison SA, Torgerson S, Hayashi P, Ward J, Schenker S. Vitamin E
and vitamin C treatment improves fibrosis in patients with nonalcoholic
steatohepatitis. Am J Gastroenterol 2003;98:2485-2490.
47. Bendich A, Machlin LJ. Safety of oral intake of vitamin E. Am J Clin
48. Miller ER 3rd, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ,
Guallar E. Meta-analysis: high-dosage vitamin E supplementation may
increase all-cause mortality. Ann Intern Med 2005;142:37-46.
49. Lindor KD, Kowdley KV, Heathcote EJ, Harrison ME, Jorgensen R,
Angulo P, et al. Ursodeoxycholic acid for treatment of nonalcoholic
steatohepatitis: results of a randomized trial. Hepatology 2004;39:
50. Leuschner UF, Lindenthal B, Herrmann G, Arnold JC, Rössle M,
Cordes HJ, et al. High-dose ursodeoxycholic acid therapy for
nonalcoholic steatohepatitis: a double-blind, randomized, placebo-
controlled trial. Hepatology 2010;52:472-479.
51. Marchesini G, Brizi M, Bianchi G, Tomassetti S, Zoli M, Melchionda N.
Metformin in non-alcoholic steatohepatitis. Lancet 2001;358:893-894.
52. Misbin RI, Green L, Stadel BV, Gueriguian JL, Gubbi A, Fleming GA.
Lactic acidosis in patients with diabetes treated with metformin. N Engl
J Med 1998;338:265-266.
53. Parés A, Caballería L, Rodés J. Excellent long-term survival in patients
with primary biliary cirrhosis and biochemical response to ursodeoxy-
cholic acid. Gastroenterology 2006;130:715-720.
54. Poupon RE, Balkau B, Eschwège E, Poupon R. A multicenter,
controlled trial of ursodiol for the treatment of primary biliary cirrhosis.
UDCA-PBC Study Group. N Engl J Med 1991;324:1548-1554.
55. Poupon RE, Poupon R, Balkau B. Ursodiol for the long-term treatment
of primary biliary cirrhosis. The UDCA-PBC Study Group. N Engl J
56. Poupon RE, Lindor KD, Cauch-Dudek K, Dickson ER, Poupon R,
Heathcote EJ. Combined analysis of randomized controlled trials of
ursodeoxycholic acid in primary biliary cirrhosis. Gastroenterology
57. Rust C, Sauter GH, Oswald M, Büttner J, Kullak-Ublick GA,
Paumgartner G, et al. Effect of cholestyramine on bile acid pattern and
synthesis during administration of ursodeoxycholic acid in man. Eur J
Clin Invest 2000;30:135-139.
58. Giannini EG, Zaman A, Kreil A, Floreani A, Dulbecco P, Testa E, et al.
Platelet count/spleen diameter ratio for the noninvasive diagnosis of
esophageal varices: results of a multicenter, prospective, validation
study. Am J Gastroenterol 2006;101:2511-2519.
59. Bosch J, Abraldes JG. Variceal bleeding: pharmacological therapy. Dig
60. Franchis R, Dellera A, Fazzini L, Zatelli S, Savojardo V, Primignani M.
Evaluation and follow-up of patients with portal hypertension and
oesophageal varices: how and when. Dig Liver Dis 2001;33:643-646.
61. de Franchis R, Pascal JP, Ancona E, Burroughs AK, Henderson M, Fleig
W, et al. Definitions, methodology and therapeutic strategies in portal
hypertension. A Consensus Development Workshop, Baveno, Lake
Maggiore, Italy, April 5 and 6, 1990. J Hepatol 1992;15:256-261.
62. Beppu K, Inokuchi K, Koyanagi N, Nakayama S, Sakata H, Kitano S, et
al. Prediction of variceal hemorrhage by esophageal endoscopy.
Gastrointest Endosc 1981;27:213-218.
63. Grace ND, Groszmann RJ, Garcia-Tsao G, Burroughs AK, Pagliaro L,
Makuch RW, et al. Portal hypertension and variceal bleeding: an
AASLD single topic symposium. Hepatology 1998;28:868-880.
64. Garcia-Tsao G, Sanyal AJ, Grace ND, Carey W; Practice Guidelines
Committee of the American Association for the Study of Liver
Diseases; Practice Parameters Committee of the American College of
Gastroenterology. Prevention and management of gastroesophageal
varices and variceal hemorrhage in cirrhosis. Hepatology 2007;46:
65. Abraldes JG, Bosch J. Somatostatin and analogues in portal
hypertension. Hepatology 2002;35:1305-1312.
66. Garcia-Tsao G, Bosch J. Management of varices and variceal
hemorrhage in cirrhosis. N Engl J Med 2010;362:823-832.
67. Bernard B, Grangé JD, Khac EN, Amiot X, Opolon P, Poynard T.
Antibiotic prophylaxis for the prevention ofbacterial infections in
cirrhotic patients with gastrointestinal bleeding: a meta-analysis.
68. Bañares R, Albillos A, Rincón D, Alonso S, González M, Ruiz-del-
Arbol L, et al. Endoscopic treatment versus endoscopic plus
pharmacologic treatment for acute variceal bleeding: a meta-analysis.
69. Groszmann RJ, Garcia-Tsao G, Bosch J, Grace ND, Burroughs AK,
Planas R, et al. Beta-blockers to prevent gastroesophageal varices in
patients with cirrhosis. N Engl J Med 2005;353:2254-2261.
70. de Franchis R; Baveno V Faculty. Revising consensus in portal
hypertension: report of the Baveno V consensus workshop on
methodology of diagnosis and therapy in portal hypertension. J Hepatol
71. D'Amico G, Pagliaro L, Bosch J. Pharmacological treatment of portal
hypertension: an evidence-based approach. Semin Liver Dis 1999;
72. de Franchis R. Updating consensus in portal hypertension: report of the
Baveno III Consensus Workshop on definitions, methodology and
therapeutic strategies in portal hypertension. J Hepatol 2000;33:
73. Suk KT, Kim MY, Park DH, Kim KH, Jo KW, Hong JH, et al. Effect of
propranolol on portal pressure and systemic hemodynamics in patients
with liver cirrhosis and portal hypertension: a prospective study. Gut
74. Khuroo MS, Khuroo NS, Farahat KL, Khuroo YS, Sofi AA, Dahab ST.
Meta-analysis: endoscopic variceal ligation for primary prophylaxis of
18 The Korean Journal of Hepatology Vol. 18. No. 1, March 2012
oesophageal variceal bleeding. Aliment Pharmacol Ther 2005;21:
75. Garcia-Pagán JC, Bosch J. Endoscopic band ligation in the treatment of
portal hypertension. Nat Clin Pract Gastroenterol Hepatol 2005;2:
76. Kumar A, Jha SK, Sharma P, Dubey S, Tyagi P, Sharma BC, et al.
Addition of propranolol and isosorbide mononitrate to endoscopic
variceal ligation does not reduce variceal rebleeding incidence.
Gastroenterology 2009;137:892-901, 901.e1.
77. Tripathi D, Ferguson JW, Kochar N, Leithead JA, Therapondos G,
McAvoy NC, et al. Randomized controlled trial of carvedilol versus
variceal band ligation for the prevention of the first variceal bleed.
78. Sarin SK, Wadhawan M, Agarwal SR, Tyagi P, Sharma BC. Endoscopic
variceal ligation plus propranolol versus endoscopic variceal ligation
alone in primary prophylaxis of variceal bleeding. Am J Gastroenterol
79. Gournay J, Masliah C, Martin T, Perrin D, Galmiche JP. Isosorbide
mononitrate and propranolol compared with propranolol alone for the
prevention of variceal rebleeding. Hepatology 2000;31:1239-1245.
80. Laine L, Cook D. Endoscopic ligation compared with sclerotherapy for
treatment of esophageal variceal bleeding. A meta-analysis. Ann Intern
81. Lo GH, Lai KH, Cheng JS, Chen MH, Huang HC, Hsu PI, et al.
Endoscopic variceal ligation plus nadolol and sucralfate compared with
ligation alone for the prevention of variceal rebleeding: a prospective,
randomized trial. Hepatology 2000;32:461-465.
82. de la Peña J, Brullet E, Sanchez-Hernández E, Rivero M, Vergara M,
Martin-Lorente JL, et al. Variceal ligation plus nadolol compared with
ligation for prophylaxis of variceal rebleeding: a multicenter trial.
83. Boyer TD, Haskal ZJ; American Association for the Study of Liver
Diseases. The role of transjugular intrahepatic portosystemic shunt in
the management of portal hypertension. Hepatology 2005;41:386-400.
84. Henderson JM. Salvage therapies for refractory variceal hemorrhage.
Clin Liver Dis 2001;5:709-725.
85. Wright AS, Rikkers LF. Current management of portal hypertension. J
Gastrointest Surg 2005;9:992-1005.
86. Thalheimer U, Mela M, Patch D, Burroughs AK. Prevention of variceal
rebleeding. Lancet 2003;361:2244-2245.
87. Sarin SK, Lahoti D, Saxena SP, Murthy NS, Makwana UK. Prevalence,
classification and natural history of gastric varices: a long-term
follow-up study in 568 portal hypertension patients. Hepatology
88. Lo GH, Lai KH, Cheng JS, Huang RL, Wang SJ, Chiang HT. Prevalence
of paraesophageal varices and gastric varices in patients achieving
variceal obliteration by banding ligation and by injection sclerotherapy.
Gastrointest Endosc 1999;49:428-436.
89. Shiha G, El-Sayed SS. Gastric variceal ligation: a new technique.
Gastrointest Endosc 1999;49:437-441.
90. Lee TH, Shih LN. Clinical experience of endoscopic banding ligation
for bleeding gastric varices. Hepatogastroenterology 2008;55:766-769.
91. Kim JW, Baik SK, Kim KH, Kim HJ, Jo KW, Hong JH, et al. Effect of
endoscopic sclerotherapy using N-butyl-2-cyanoacrylate in patients
with gastric variceal bleeding. Korean J Hepatol 2006;12:394-403.
92. Joo HS, Jang JY, Eun SH, Kim SK, Jung IS, Ryu CB, et al. Long-term
results of endoscopic histoacryl (N-butyl-2-cyanoacrylate) injection
for treatment of gastric varices-a 10-year experience. Korean J
93. Lo GH, Lai KH, Cheng JS, Chen MH, Chiang HT. A prospective,
randomized trial of butyl cyanoacrylate injection versus band ligation in
the management of bleeding gastric varices. Hepatology 2001;33:
94. Huang YH, Yeh HZ, Chen GH, Chang CS, Wu CY, Poon SK, et al.
Endoscopic treatment of bleeding gastric varices by N-butyl-2-
cyanoacrylate (Histoacryl) injection: long-term efficacy and safety.
Gastrointest Endosc 2000;52:160-167.
95. Akahoshi T, Hashizume M, Shimabukuro R, Tanoue K, Tomikawa M,
Okita K, et al. Long-term results of endoscopic Histoacryl injection
sclerotherapy for gastric variceal bleeding: a 10-year experience.
Surgery 2002;131(Suppl):S176- S181.
96. Seewald S, Ang TL, Imazu H, Naga M, Omar S, Groth S, et al. A
standardized injection technique and regimen ensures success and
safety of N-butyl-2-cyanoacrylate injection for the treatment of gastric
fundal varices (with videos). Gastrointest Endosc 2008;68:447-454.
97. Kim T, Shijo H, Kokawa H, Tokumitsu H, Kubara K, Ota K, et al. Risk
factors for hemorrhage from gastric fundal varices. Hepatology 1997;
98. Oho K, Iwao T, Sumino M, Toyonaga A, Tanikawa K. Ethanolamine
oleate versus butyl cyanoacrylate for bleeding gastric varices: a
nonrandomized study. Endoscopy 1995;27:349-354.
99. Sarin SK, Jain AK, Jain M, Gupta R. A randomized controlled trial of
cyanoacrylate versus alcohol injection in patients with isolated fundic
varices. Am J Gastroenterol 2002;97:1010-1015.
100. Korula J, Chin K, Ko Y, Yamada S. Demonstration of two distinct
subsets of gastric varices. Observations during a seven-year study of
endoscopic sclerotherapy. Dig Dis Sci 1991;36:303-309.
101. Mahadeva S, Bellamy MC, Kessel D, Davies MH, Millson CE.
Cost-effectiveness of N-butyl-2-cyanoacrylate (histoacryl) glue
injections versus transjugular intrahepatic portosystemic shunt in the
management of acute gastric variceal bleeding. Am J Gastroenterol
102. Noh DY, Park SY, Joo SY, Park CH, Lee WS, Joo YE, et al.
Therapeutic effect of the endoscopic N-butyl-2-cyanoacrylate injection
for acute esophagogastric variceal bleeding: comparison with
transjugular intrahepatic portosystemic shunt. Korean J Gastroenterol
103. Choi YH, Yoon CJ, Park JH, Chung JW, Kwon JW, Choi GM.
Balloon-occluded retrograde transvenous obliteration for gastric
variceal bleeding: its feasibility compared with transjugular
intrahepatic portosystemic shunt. Korean J Radiol 2003;4:109-116.
104. Baik GH, Kim DJ, Lee HG, Min SK, Kong SJ, Kim JB, et al.
Therapeutic efficacy of balloon-occluded retrograde transvenous
obliteration in the treatment of gastric varices in cirrhotic patients with
gastrorenal shunt. Korean J Gastroenterol 2004;43:196-203.
105. Hirota S, Matsumoto S, Tomita M, Sako M, Kono M. Retrograde
transvenous obliteration of gastric varices. Radiology 1999;211:
106. Kim ES, Park SY, Kwon KT, Lee DS, Park MJ, Chung IK, et al. The
clinical usefulness of balloon occluded retrograde transvenous
obliteration in gastric variceal bleeding. Korean J Hepatol 2003;
107. Henderson JM, Boyer TD, Kutner MH, Galloway JR, Rikkers LF,
Jeffers LJ, et al. Distal splenorenal shunt versus transjugular
intrahepatic portal systematic shunt for variceal bleeding: a
randomized trial. Gastroenterology 2006;130:1643-1651.
108. Mishra SR, Sharma BC, Kumar A, Sarin SK. Primary prophylaxis of
gastric variceal bleeding comparing cyanoacrylate injection and
beta-blockers: a randomized controlled trial. J Hepatol 2011;54:
109. Spina GP, Arcidiacono R, Bosch J, Pagliaro L, Burroughs AK,
Santambrogio R, et al. Gastric endoscopic features in portal
hypertension: final report of a consensus conference, Milan, Italy,
September 19, 1992. J Hepatol 1994;21:461-467.
Ki Tae Suk, et al. Revision and update on clinical practice guideline for liver cirrhosis 19
110. Kim MY, Choi H, Baik SK, Yea CJ, Won CS, Byun JW, et al. Portal
hypertensive gastropathy: correlation with portal hypertension and
prognosis in cirrhosis. Dig Dis Sci 2010;55:3561-3567.
111. Pérez-Ayuso RM, Piqué JM, Bosch J, Panés J, González A, Pérez R, et
al. Propranolol in prevention of recurrent bleeding from severe portal
hypertensive gastropathy in cirrhosis. Lancet 1991;337:1431-1434.
112. Urata J, Yamashita Y, Tsuchigame T, Hatanaka Y, Matsukawa T, Sumi
S, et al. The effects of transjugular intrahepatic portosystemic shunt on
portal hypertensive gastropathy. J Gastroenterol Hepatol 1998;13:
113. Ginés P, Quintero E, Arroyo V, Terés J, Bruguera M, Rimola A, et al.
Compensated cirrhosis: natural history and prognostic factors.
114. Han YS, Kim BH, Baek IY, Lee DK, Kim KJ, Dong SH, et al. The
change of the etiology, complications and cause of death of the liver
cirrhosis in 1990s. Korean J Hepatol 2000;6:328-339.
115. Hwangbo Y, Jung JH, Shim J, Kim BH, Jung SH, Lee CK, et al.
Etiologic and laboratory analyses of ascites in patients who underwent
diagnostic paracentesis. Korean J Hepatol 2007;13:185-195.
116. Kuiper JJ, de Man RA, van Buuren HR. Review article: Management
of ascites and associated complications in patients with cirrhosis.
Aliment Pharmacol Ther 2007;26(Suppl 2):183-193.
117. Rimola A, García-Tsao G, Navasa M, Piddock LJ, Planas R, Bernard
B, et al. Diagnosis, treatment and prophylaxis of spontaneous bacterial
peritonitis: a consensus document. International Ascites Club. J
118. Bernardi M, Laffi G, Salvagnini M, Azzena G, Bonato S, Marra F, et
al. Efficacy and safety of the stepped care medical treatment of ascites
in liver cirrhosis: a randomized controlled clinical trial comparing two
diets with different sodium content. Liver 1993;13:156-162.
119. Angeli P, Wong F, Watson H, Ginès P; CAPPS Investigators.
Hyponatremia in cirrhosis: Results of a patient population survey.
120. The Korean Association for The Study of The Liver. Treatment
guideline of complications of liver cirrhosis. Korean J Hepatol
121. Reynolds TB. Ascites. Clin Liver Dis 2000;4:151-168, vii.
122. Santos J, Planas R, Pardo A, Durández R, Cabré E, Morillas RM, et al.
Spironolactone alone or in combination with furosemide in the
treatment of moderate ascites in nonazotemic cirrhosis. A randomized
comparative study of efficacy and safety. J Hepatol 2003;39:187-192.
123. Bernardi M. Optimum use of diuretics in managing ascites in patients
with cirrhosis. Gut 2010;59:10-11.
124. Angeli P, Fasolato S, Mazza E, Okolicsanyi L, Maresio G, Velo E, et
al. Combined versus sequential diuretic treatment of ascites in
non-azotaemic patients with cirrhosis: results of an open randomised
clinical trial. Gut 2010;59:98-104.
125. European Association for the Study of the Liver. EASL clinical
practice guidelines on the management of ascites, spontaneous bacterial
peritonitis, and hepatorenal syndrome in cirrhosis. J Hepatol 2010;
126. Runyon BA; AASLD Practice Guidelines Committee. Management of
adult patients with ascites due to cirrhosis: an update. Hepatology
127. Stiehm AJ, Mendler MH, Runyon BA. Detection of diuretic-resistace
or diuretic-sensitivity by the spot urine Na/K ratio in 729 specimens
from cirrhotics with ascites: approximately 90% accuracy as
compared to 24-hr urine Na excretion. [Abstract]. Hepatology 2002;
128. Moore KP, Aithal GP. Guidelines on the management of ascites in
cirrhosis. Gut 2006;55(Suppl 6):vi1- vi 12.
129. Hong SP, Eun YG, Kim HJ, Kim BH, Chang YW, Lee JI, et al. Effects
of large volume paracentesis. Korean J Intern Med 1991;40:147-152.
130. Arroyo V, Ginès P, Gerbes AL, Dudley FJ, Gentilini P, Laffi G, et al.
Definition and diagnostic criteria of refractory ascites and hepatorenal
syndrome in cirrhosis. International Ascites Club. Hepatology 1996;
131. Moreau R, Valla DC, Durand-Zaleski I, Bronowicki JP, Durand F,
Chaput JC, et al. Comparison of outcome in patients with cirrhosis and
ascites following treatment with albumin or a synthetic colloid: a
randomised controlled pilot trail. Liver Int 2006;26:46-54.
132. Singh V, Dheerendra PC, Singh B, Nain CK, Chawla D, Sharma N, et
al. Midodrine versus albumin in the prevention of paracentesis-
induced circulatory dysfunction in cirrhotics: a randomized pilot
study. Am J Gastroenterol 2008;103:1399-1405.
133. Singh V, Kumar B, Nain CK, Singh B, Sharma N, Bhalla A, et al.
Noradrenaline and albumin in paracentesis-induced circulatory
dysfunction in cirrhosis: a randomized pilot study. J Intern Med
134. Lata J, Marecek Z, Fejfar T, Zdenek P, Brůha R, Safka V, et al. The
efficacy of terlipressin in comparison with albumin in the prevention
of circulatory changes after the paracentesis of tense ascites-a
randomized multicentric study. Hepatogastroenterology 2007;54:
135. Heuman DM, Abou-Assi SG, Habib A, Williams LM, Stravitz RT,
Sanyal AJ, et al. Persistent ascites and low serum sodium identify
patients with cirrhosis and low MELD scores who are at high risk for
early death. Hepatology 2004;40:802-810.
136. Kim YS. Ascites, hepatorenal syndrome and spontaneous bacterial
peritonitis in patients with portal hypertension. Korean J Gastroenterol
137. Cardenas A, Gines P. Pathogenesis and treatment of dilutional
hyponatremia in cirrhosis. In: Arroyo V, ed. Progress in the treatment
of liver diseases. Barcelona: Ars Medica, 2003:31-42.
138. Jalan R, Mookerjee R, Cheshire L, Williams R, Davies N. Albumin
infusion for severe hyponatremia in patients with refractory ascites: A
randomized clinical trail. [Abstract]. J Hepatol 2007;46(Suppl):232A.
139. Ginès P, Guevara M. Hyponatremia in cirrhosis: pathogenesis, clinical
significance, and management. Hepatology 2008;48:1002-1010.
140. Ruiz-del-Arbol L, Monescillo A, Arocena C, Valer P, Ginès P, Moreira
V, et al. Circulatory function and hepatorenal syndrome in cirrhosis.
141. Ruiz-del-Arbol L, Urman J, Fernández J, González M, Navasa M,
Monescillo A, et al. Systemic, renal, and hepatic hemodynamic
derangement in cirrhotic patients with spontaneous bacterial
peritonitis. Hepatology 2003;38:1210-1218.
142. Arroyo V, Colmenero J. Ascites and hepatorenal syndrome in
cirrhosis: pathophysiological basis of therapy and current management.
J Hepatol 2003;38(Suppl 1):S69-S89.
143. Angeli P, Merkel C. Pathogenesis and management of hepatorenal
syndrome in patients with cirrhosis. J Hepatol 2008;48(Suppl 1):S93-
144. Martín-Llahí M, Pépin MN, Guevara M, Díaz F, Torre A, Monescillo
A, et al. Terlipressin and albumin vs albumin in patients with cirrhosis
and hepatorenal syndrome: a randomized study. Gastroenterology
145. Sanyal AJ, Boyer T, Garcia-Tsao G, Regenstein F, Rossaro L,
Appenrodt B, et al. A randomized, prospective, double-blind, placebo-
controlled trial of terlipressin for type 1 hepatorenal syndrome.
146. Halimi C, Bonnard P, Bernard B, Mathurin P, Mofredj A, di Martino V,
et al. Effect of terlipressin (Glypressin) on hepatorenal syndrome in
cirrhotic patients: results of a multicentre pilot study. Eur J
Gastroenterol Hepatol 2002;14:153-158.
20 The Korean Journal of Hepatology Vol. 18. No. 1, March 2012
147. Ortega R, Ginès P, Uriz J, Cárdenas A, Calahorra B, De Las Heras D,
et al. Terlipressin therapy with and without albumin for patients with
hepatorenal syndrome: results of a prospective, nonrandomized study.
148. Muñoz LE, Alcalá EG, Cordero P, Martínez MA, Vázquez NY,
Galindo S, et al. Reversal of hepatorenal syndrome in cirrhotic
patients with terlipressin plus albumin. First experience in Mexico.
Ann Hepatol 2009;8:207-211.
149. Danalioglu A, Cakaloglu Y, Karaca C, Aksoy N, Akyuz F, Ozdil S, et
al. Terlipressin and albumin combination treatment in hepatorenal
syndrome. Hepatogastroenterology 2003;50(Suppl 2):ccciii-cccv.
150. Moreau R, Durand F, Poynard T, Duhamel C, Cervoni JP, Ichaï P, et al.
Terlipressin in patients withcirrhosis and type 1 hepatorenal syndrome:
a retrospective multicenter study. Gastroenterology 2002;122:923-930.
151. Colle I, Durand F, Pessione F, Rassiat E, Bernuau J, Barrière E, et al.
Clinical course, predictive factors and prognosis in patients with
cirrhosis and type 1 hepatorenal syndrome treated with Terlipressin: a
retrospective analysis. J Gastroenterol Hepatol 2002;17:882-888.
152. Neri S, Pulvirenti D, Malaguarnera M, Cosimo BM, Bertino G,
Ignaccolo L, et al. Terlipressin and albumin in patients with cirrhosis
and type I hepatorenal syndrome. Dig Dis Sci 2008;53:830-835.
153. Mulkay JP, Louis H, Donckier V, Bourgeois N, Adler M, Deviere J, et
al. Long-term terlipressin administration improves renal function in
cirrhotic patients with type 1 hepatorenal syndrome: a pilot study.
Acta Gastroenterol Belg 2001;64:15-19.
154. Ganne-Carrié N, Hadengue A, Mathurin P, Durand F, Erlinger S,
Benhamou JP. Hepatorenal syndrome. Long-term treatment with
terlipressin as a bridge to liver transplantation. Dig Dis Sci 1996;
155. Duvoux C, Zanditenas D, Hézode C, Chauvat A, Monin JL, Roudot-
Thoraval F, et al. Effects of noradrenalin and albumin in patients with
type I hepatorenal syndrome: a pilot study. Hepatology 2002;36:
156. Alessandria C, Ottobrelli A, Debernardi-Venon W, Todros L, Cerenzia
MT, Martini S, et al. Noradrenalin vs terlipressin in patients with
hepatorenal syndrome: a prospective, randomized, unblinded, pilot
study. J Hepatol 2007;47:499-505.
157. Wong F, Pantea L, Sniderman K. Midodrine, octreotide, albumin, and
TIPS in selected patients with cirrhosis and type 1 hepatorenal
syndrome. Hepatology 2004;40:55-64.
158. Esrailian E, Pantangco ER, Kyulo NL, Hu KQ, Runyon BA.
Octreotide/Midodrine therapy significantly improves renal function
and 30-day survival in patients with type 1 hepatorenal syndrome. Dig
Dis Sci 2007;52:742-748.
159. Skagen C, Einstein M, Lucey MR, Said A. Combination treatment
with octreotide, midodrine, and albumin improves survival in patients
with type 1 and type 2 hepatorenal syndrome. J Clin Gastroenterol
160. Kalambokis G, Economou M, Fotopoulos A, Al Bokharhii J, Pappas
C, Katsaraki A, et al. The effects of chronic treatment with octreotide
versus octreotide plus midodrine on systemic hemodynamics and
renal hemodynamics and function in nonazotemic cirrhotic patients
with ascites. Am J Gastroenterol 2005;100:879-885.
161. Narahara Y, Kanazawa H, Taki Y, Kimura Y, Atsukawa M, Katakura
T, et al. Effects of terlipressin on systemic, hepatic and renal
hemodynamics in patients with cirrhosis. J Gastroenterol Hepatol
162. Baik SK, Jeong PH, Ji SW, Yoo BS, Kim HS, Lee DK, et al. Acute
hemodynamic effects of octreotide and terlipressin in patients with
cirrhosis: a randomized comparison. Am J Gastroenterol 2005;100:
163. Alessandria C, Venon WD, Marzano A, Barletti C, Fadda M, Rizzetto
M. Renal failure in cirrhotic patients: role of terlipressin in clinical
approach to hepatorenal syndrome type 2. Eur J Gastroenterol Hepatol
164. Testro AG, Wongseelashote S, Angus PW, Gow PJ. Long-term
outcome of patients treated with terlipressin for types 1 and 2
hepatorenal syndrome. J Gastroenterol Hepatol 2008;23:1535-1540.
165. Guevara M, Ginès P, Bandi JC, Gilabert R, Sort P, Jiménez W, et al.
Transjugular intrahepatic portosystemic shunt in hepatorenal syndrome:
effects on renal function and vasoactive systems. Hepatology 1998;
166. Brensing KA, Textor J, Perz J, Schiedermaier P, Raab P, Strunk H, et
al. Long term outcome after transjugular intrahepatic portosystemic
stent-shunt in non-transplant cirrhotics with hepatorenal syndrome: a
phase II study. Gut 2000;47:288-295.
167. Mitzner SR, Stange J, Klammt S, Risler T, Erley CM, Bader BD, et al.
Improvement of hepatorenal syndrome with extracorporeal albumin
dialysis MARS: results of a prospective, randomized, controlled
clinical trial. Liver Transpl 2000;6:277-286.
168. Witzke O, Baumann M, Patschan D, Patschan S, Mitchell A, Treichel
U, et al. Which patients benefit from hemodialysis therapy in
hepatorenal syndrome? J Gastroenterol Hepatol 2004;19:1369-1373.
169. Capling RK, Bastani B. The clinical course of patients with type 1
hepatorenal syndrome maintained on hemodialysis. Ren Fail 2004;
170. Sola-Vera J, Miñana J, Ricart E, Planella M, González B, Torras X, et
al. Randomized trial comparing albumin and saline in the prevention
of paracentesis-induced circulatory dysfunction in cirrhotic patients
with ascites. Hepatology 2003;37:1147-1153.
171. Singh V, Kumar R, Nain CK, Singh B, Sharma AK. Terlipressin versus
albumin in paracentesis-induced circulatory dysfunction in cirrhosis:
a randomized study. J Gastroenterol Hepatol 2006;21:303-307.
172. Sort P, Navasa M, Arroyo V, Aldeguer X, Planas R, Ruiz-del-Arbol L,
et al. Effect of intravenous albumin on renal impairment and mortality
in patients with cirrhosis and spontaneous bacterial peritonitis. N Engl
J Med 1999;341:403-409.
173. Sigal SH, Stanca CM, Fernandez J, Arroyo V, Navasa M. Restricted
use of albumin for spontaneous bacterial peritonitis. Gut 2007;56:
174. Fernández J, Navasa M, Planas R, Montoliu S, Monfort D, Soriano G,
et al. Primary prophylaxis of spontaneous bacterial peritonitis delays
hepatorenal syndrome and improves survival in cirrhosis. Gastro-
175. Akriviadis E, Botla R, Briggs W, Han S, Reynolds T, Shakil O.
Pentoxifylline improves short-term survival in severe acute alcoholic
hepatitis: a double-blind, placebo-controlled trial. Gastroenterology
176. Assimakopoulos SF, Thomopoulos KC, Labropoulou-Karatza C.
Pentoxifylline: a first line treatment option for severe alcoholic
hepatitis and hepatorenal syndrome? World J Gastroenterol 2009;15:
177. De BK, Gangopadhyay S, Dutta D, Baksi SD, Pani A, Ghosh P.
Pentoxifylline versus prednisolone for severe alcoholic hepatitis: a
randomized controlled trial. World J Gastroenterol 2009;15:
178. Heo J, Seo YS, Yim HJ, Hahn T, Park SH, Ahn SH, et al. Clinical
featuresand prognosis of spontaneous bacterial peritonitis in korean
patients with liver cirrhosis: a multicenter retrospective study. Gut
179. Ginès P, Cárdenas A. The management of ascites and hyponatremia in
cirrhosis. Semin Liver Dis 2008;28:43-58.
180. Ferenci P, Lockwood A, Mullen K, Tarter R, Weissenborn K, Blei AT.
Hepatic encephalopathy--definition, nomenclature, diagnosis, and
Ki Tae Suk, et al. Revision and update on clinical practice guideline for liver cirrhosis 21 Download full-text
quantification: final report of the working party at the 11th World
Congresses of Gastroenterology, Vienna, 1998. Hepatology 2002;35:
181. Weissenborn K, Ennen JC, Schomerus H, Rückert N, Hecker H.
Neuropsychological characterization of hepatic encephalopathy. J
182. Fessel JN. An analysis of the causes and prevention of hepatic coma.
183. Blei AT, Córdoba J; Practice Parameters Committee of the American
College of Gastroenterology. Hepatic Encephalopathy. Am J
184. Stahl J. Studies of the blood ammonia in liver disease. Its diagnostic,
prognostic, and therapeutic significance. Ann Intern Med 1963;58:1-24.
185. Krieger D, Krieger S, Jansen O, Gass P, Theilmann L, Lichtnecker H.
Manganese and chronic hepatic encephalopathy. Lancet 1995;346:
186. Garcia-Tsao G, Lim JK; Members of Veterans Affairs Hepatitis C
Resource Center Program. Management and treatment of patients
with cirrhosis and portal hypertension: recommendations from the
Department of Veterans Affairs Hepatitis C Resource Center Program
and the National Hepatitis C Program. Am J Gastroenterol 2009;
187. Als-Nielsen B, Gluud LL, Gluud C. Non-absorbable disaccharides for
hepatic encephalopathy: systematic review of randomised trials. BMJ
188. Prasad S, Dhiman RK, Duseja A, Chawla YK, Sharma A, Agarwal R.
Lactulose improves cognitive functions and health-related quality of
life in patients with cirrhosis who have minimal hepatic ence-
phalopathy. Hepatology 2007;45:549-559.
189. Sharma BC, Sharma P, Agrawal A, Sarin SK. Secondary prophylaxis
of hepatic encephalopathy: an open-label randomized controlled trial
of lactulose versus placebo. Gastroenterology 2009;137:885-891,
190. Phongsamran PV, Kim JW, Cupo Abbott J, Rosenblatt A.
Pharmacotherapy for hepatic encephalopathy. Drugs 2010;70:
191. Mas A, Rodés J, Sunyer L, Rodrigo L, Planas R, Vargas V, et al.
Comparison of rifaximin and lactitol in the treatment of acute hepatic
encephalopathy: results of a randomized, double-blind, double-
dummy, controlled clinical trial. J Hepatol 2003;38:51-58.
192. Massa P, Dodero M. Treatment of hepatic encephalopathy with
rifaximin: double-blind, double-dummy study versus lactulose. J Clin
193. Paik YH, Lee KS, Han KH, Song KH, Kim MH, Moon BS, et al.
Comparison of rifaximin and lactulose for the treatment of hepatic
encephalopathy: a prospective randomized study. Yonsei Med J
194. Stewart CA, Malinchoc M, Kim WR, Kamath PS. Hepatic
encephalopathy as a predictor of survival in patients with end-stage
liver disease. Liver Transpl 2007;13:1366-1371.
195. Bajaj JS, Sanyal AJ, Bell D, Gilles H, Heuman DM. Predictors of the
recurrence of hepatic encephalopathy in lactulose-treated patients.
Aliment Pharmacol Ther 2010;31:1012-1017.
196. Bass NM, Mullen KD, Sanyal A, Poordad F, Neff G, Leevy CB, et al.
Rifaximin treatment in hepatic encephalopathy. N Engl J Med
197. Dhiman RK, Saraswat VA, Sharma BK, Sarin SK, Chawla YK,
Butterworth R, et al. Minimal hepatic encephalopathy: consensus
statement of a working party of the Indian National Association for
Study of the Liver. J Gastroenterol Hepatol 2010;25:1029-1041.
198. Groeneweg M, Quero JC, De Bruijn I, Hartmann IJ, Essink-bot ML,
Hop WC, et al. Subclinical hepatic encephalopathy impairs daily
functioning. Hepatology 1998;28:45-49.
199. Folstein MF, Folstein SE, McHugh PR. "Mini-mental state". A
practical method for grading the cognitive state of patients for the
clinician. J Psychiatr Res 1975;12:189-198.
200. Romero-Gómez M, Córdoba J, Jover R, del Olmo JA, Ramírez M, Rey
R, et al. Value of the critical flicker frequency in patients with minimal
hepatic encephalopathy. Hepatology 2007;45:879-885.
201. Dhiman RK, Kurmi R, Thumburu KK, Venkataramarao SH, Agarwal
R, Duseja A, et al. Diagnosis and prognostic significance of minimal
hepatic encephalopathy in patients with cirrhosis of liver. Dig Dis Sci
202. Seo YS, Um SH, Jung ES, Kim JH, Kim JH, An SH, et al. Detection of
minimal hepatic encephalopathy using the Psychometric Hepatic
Encephalopathy Score in Korean patients with liver cirrhosis.
[Abstract]. Hepatology 2010;52(Suppl):919A.
203. Bajaj JS, Saeian K, Christensen KM, Hafeezullah M, Varma RR,
Franco J, et al. Probiotic yogurt for the treatment of minimal hepatic
encephalopathy. Am J Gastroenterol 2008;103:1707-1715.
204. Kircheis G, Nilius R, Held C, Berndt H, Buchner M, Görtelmeyer R, et
al. Therapeutic efficacy of L-ornithine-L-aspartate infusions in
patients with cirrhosis and hepatic encephalopathy: results of a
placebo-controlled, double-blind study. Hepatology 1997;25:1351-1360.
205. Malaguarnera M, Gargante MP, Cristaldi E, Vacante M, Risino C,
Cammalleri L, et al. Acetyl-L-carnitine treatment in minimal hepatic
encephalopathy. Dig Dis Sci 2008;53:3018-3025.
206. Moore KP, Wong F, Gines P, Bernardi M, Ochs A, Salerno F, et al. The
management of ascites in cirrhosis: report on the consensus conference
of the International Ascites Club. Hepatology 2003;38:258-266.