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Guidelines of prevention and treatment for alcoholic liver disease
(2018, China)
You Ming Li,1 Jian Gao Fan,
2 on behalf of the National Workshop on Fatty Liver and
Alcoholic Liver Disease, Chinese Society of Hepatology, Chinese Medical
Association; Fatty Liver Disease Expert Committee, Chinese Medical Doctor
Association
1Department of Gastroenterology, The First Affiliated Hospital, College of Medicine,
Zhejiang University, Hangzhou, Zhejiang Province, 2Department of Gastroenterology,
XinHua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai Key
Laboratory of Children’s Digestion and Nutrition, Shanghai, China
Correspondence:
You Ming Li, Department of Gastroenterology, The First Affiliated Hospital, College
of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou, Zhejiang Province
310006, China. Email: [email protected]; or Jian Gao Fan, Department of
Gastroenterology, XinHua Hospital, Shanghai Jiaotong University School of
Medicine, Shanghai Key Laboratory of Children’s Digestion and Nutrition, 1665
Kongjiang Road, Shanghai 200092, China. Email: [email protected]
KEY WORDS: alcoholic liver disease, diagnosis, therapy, guidebooks
Conflict of interest: None.
Running title: Chinese guidelines for ALD (2018 update)
The guidelines have been published in Chinese on the Chinese Journal of Hepatology
2018;26(3):188-194.
This article is protected by copyright. All rights reserved.
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/cdd.12687
http://guide.medlive.cn/
1. INTRODUCTION
Alcoholic liver disease (ALD), induced by long-term heavy alcohol consumption,
encompasses a progressive clinical–histological spectrum of liver injuries from simple
fatty liver to alcoholic hepatitis, hepatic fibrosis and cirrhosis. Excessive alcohol
consumption may lead to extensive hepatocellular necrosis, and in severe cases to
liver failure. ALD is one of the most common liver diseases in China, posing a heavy
burden to public health. The guidelines, as an update from the 2010 version, provide a
more standardized and up-to-date approach to the prevention and treatment of ALD,
with reference to the latest researches and consensuses both at home and abroad. The
guidelines were developed by the National Workshop on Fatty Liver and Alcoholic
Liver Disease, Chinese Society of Hepatology, Chinese Medical Association, in
conjunction with the Fatty Liver Disease Expert Committee, Chinese Medical Doctor
Association. In the guidelines, quality of evidence (A, B and C) and strength of each
recommendation (1 and 2) are rated according to the Grading of Recommendations
Assessment, Development and Evaluation (GRADE) system (Table 1).
Table 1. Evidence quality and grades of strength of recommendation of the Grading of
Recommendations Assessment, Development and Evaluation (GRADE) system1
Grade Symbol Details
Evidence
High quality A Further research is less likely to change the confidence
in the estimated effect.
Moderate quality B Further research is likely to have an important impact
on the confidence in the estimated effect.
Low quality C Further research is most likely to have an important
impact on the confidence in the estimated effect and
may change the estimated effect.
Recommendation
Strong 1 The final recommendation is based on the quality of
evidence, patient's prognosis and treatment costs.
Weak 2 The final recommendation is based on evidence with
mixed values, uncertainties and higher costs.
The guidelines, rather than mandatory standards, are intended to assist clinicians in
making appropriate decisions on the diagnosis and treatment of ALD patients. Clinical
management should be tailored for each specific individual, in consideration of
optimal clinical evidence, medical resources currently available, exact conditions and
requirements of each patient, as well as personal knowledge and experience of the
decision-maker. As research work on ALD is progressing rapidly, the current
guidelines anticipate renewal and further improvement.
2. EPIDEMIOLOGY OF ALD
Despite a lack of nationwide epidemiological data about ALD, endemic investigations
have shown an escalating trend in the proportion of drinkers and the prevalence of
ALD in China. An epidemiological investigation conducted in North China showed
that from the early 1980s to the early 1990s, the proportion of heavy drinkers in
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general population had risen from 0.21% to 14.3%.2 At the beginning of this century, ,
the number was 26.98% in Northeast China,3 and in some areas, as high as 42.76%.
4
In South, Central and West China, the proportion of drinkers ranged from 30.9% to
43.4%.2,5–7
Some heavy drinkers or binge drinkers may be confronted with alcohol-related health
problems, among which ALD is the most common ethanol (alcohol)-induced organ
injury. Early in this century, epidemiological investigations carried out in some
provinces claimed the prevalence of ALD in China as 0.5–8.55%3–9
people in their
40s showed the highest number of up to over 10%.3,4
The percentage of ALD patients
in those who are hospitalized due to liver diseases keeps rising, from 2.4% in 2000 to
4.3% in 2004;10
alcohol abuse accounted for up to 24% of cirrhotic cases in 2003,
which had risen from 10.8% in 1999.11,12
ALD has become one of the most popular
chronic liver diseases in China.13
3. RISK FACTORS OF ALD
Risk factors that have been considered to be relevant to alcoholic liver injury and
ALD include dose, pattern and duration of alcohol consumption, variety of alcoholic
beverages, gender, ethnicity, obesity, hepatitis virus infection, genetic variability, and
nutritional conditions.
A threshold effect of alcohol-induced liver injury has been noted, based on
epidemiological data, that the risk of liver injury is significantly increased when the
dose or duration of alcohol consumption reaches a certain point.14,15
Yet, individual
difference could be observed in the dose–effect relationship between alcohol
consumption and liver injury.15–18
Alcoholic beverages vary; different alcoholic beverages do harm to the liver on
different degrees.19–21
Drinking pattern also plays a role in alcohol-related liver injury;
drinking on an empty stomach is more prone to cause liver injury than drinking with
meals.21
Compared to episodic or binge drinking, drinking daily is more likely to
cause severe alcoholic liver injury.22
Compared with men, women tend to be more susceptible ethanol (alcohol)-induced
liver injury. Moreover, a smaller dose or a shorter drinking duration could give rise to
more severe forms of ALD,14,23
alcoholic hepatitis and cirrhosis in females24
. Blood
alcohol concentration turns out to be significantly different in men and women after
alcohol intake at the same dose.25
Ethnicity,26
genetic variability,27,28
individual difference29
are also important risk
factors. The difference between Chinese Han population and Western population in
allele frequency and genotype distribution of ALD-predisposing genes, such as
alcohol dehydrogenase (ADH) 2, ADH3 and acetaldehyde dehydrogenase (ALDH) 2,
may partly accounts for the lower ALD incidence in heavy drinkers in China than that
in Western countries.28
Besides, not all drinkers will develop ALD, which suggests
that individual difference does exist in the susceptibility of ALD.15
The degree of malnutrition correlates closely with ALD mortality.29
Vitamin A
deficiency or a lower serum level of vitamin E can aggravate liver injury.30
A diet rich
in polyunsaturated fatty acid accelerates the progress of ALD while saturated fatty
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acid plays a protective role.31
Obesity or overweight also leads to a higher risk of
ALD progression.15
Hepatitis virus infection exerts a synergistic effect on alcohol-induced liver injury;32
drinking based on hepatitis virus infection and hepatitis B virus (HBV) or hepatitis C
virus (HCV) infection based on ALD could both accelerate the development and
progression of liver diseases.
4. CLINICAL DIAGNOSTIC CRITERIA OF ALD
(i) A history of long-term alcohol consumption is required, which is generally over 5
years, amounting to ethanol consumption of ≥40 g/day for men and ≥20 g/day
for women; or an evidence of binge drinking within 2 weeks, amounting to
ethanol consumption of >80 g/day.33
Factors such as gender and hereditary
susceptibility should be considered. Ethanol consumption (g) = alcohol
consumption (mL) × ethanol content (%) × 0.8. Such scales as the Alcohol Use
Disorders Inventory Test (AUDIT), the Michigan Alcoholism Screening Test
(MAST), the CAGE, can be used to screen for alcohol abuse and
dependence.34,35
(ii) Symptoms and signs are non-specific and variable, from asymptomatic to possible
complaints include right upper abdominal pain, inappetence, fatigue, weight loss
and jaundice. As the disease progresses, neuropsychical symptoms, spider
angioma and palmar erythema, etc., can be observed.33
(iii) Laboratory abnormalities in ALD may include elevated serum levels of aspartate
transaminase (AST), alanine transaminase (ALT), gamma-glutamyltransferase
(GGT), total bilirubin (TBIL), prothrombin time (PT), mean corpuscular volume
(MCV), and carbohydrate deficient transferrin (CDT). The ratio of AST/ALT >2,
as well as elevated GGT and MCV levels are deemed as markers of ALD.33,36–38
CDT test, although quite specific, has not been routinely applied in clinical
practice. Significant decrease in these indices could be observed after the
discontinuation of alcohol consumption, usually back to normal level within 4
weeks (though GGT presented a slower decreasing curve),39,40
which may be
helpful in the diagnosis of ALD.
(iv) Typical manifestations can be observed in liver B-type ultrasonography, X-ray
computed tomography (CT), magnetic resonance imaging (MRI) or transient
elastography (TE) examination (see the section of imaging diagnosis).41–50
(v) Absence of current infection of hepatotropic viruses, drug or toxin-induced liver
injury, autoimmune diseases, etc.33
Recommendation 1: Since there is no specific clinical diagnostic method for ALD,
possessing a history of long-term alcohol consumption is essential for identifying
alcohol as the cause of liver disease. Patients who meet the criteria i, iii and iv can be
diagnosed as ALD to the exclusion of liver diseases resulting from other causes; those
who meet the criteria i, iii and iv with evidence of current hepatitis virus infection can
be diagnosed as ALD with viral hepatitis. (A1)
Those who meet the clinical diagnostic criteria can be classified as follows.
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(vi) Mild ALD: results of liver biochemical, imaging and histopathological tests are
basically normal or slightly abnormal.
(vii) Alcoholic fatty liver: imaging results are consistent with the diagnostic criteria of
fatty liver, with or without slight abnormality of serum ALT, AST or GGT levels.
(viii) Alcoholic hepatitis: it is a clinical syndrome induced by extensive hepatocellular
necrosis within a short period of time, mainly manifested as elevated levels of serum
ALT, AST or GGT, with or without elevated TBIL level, possibly accompanied by
fever or elevated neutrophil level in peripheral blood. Severe alcoholic hepatitis can
be diagnosed when a ALD patient presents signs of liver failure, such as jaundice,
coagulation disturbance, hepatic encephalopathy, acute renal failure, upper
gastrointestinal bleeding, usually accompanied by endotoxemia.
(ix) Alcoholic hepatic fibrosis: no characteristic changes in clinical symptoms, signs,
ultrasonography or CT findings. Without liver biopsy, diagnosis should be made
through a comprehensive evaluation of drinking history, TE or MRI examination,
laboratory tests of serum markers indicating fibrosis (hyaluronic acid, type III
collagen, type IV collagen, laminin), GGT, AST/ALT, AST/platelet (PLT) ratio,
cholesterol, apolipoprotein A1, TBIL, α2-macroglobulin, ferritin, homeostatic model
assessment for insulin resistance (HOMA-IR), and so on.
(x) Alcoholic cirrhosis: clinical manifestations of cirrhosis can be seen along with its
typical changes in serum biochemical markers, TE and other imaging examinations.
5. IMAGING DIAGNOSIS OF ALD41–50
5.1. Ultrasonography
Diffuse fatty liver can be diagnosed when at least two of the following three
abdominal ultrasonographic manifestations are present: (i) diffuse enhancement of
near field echo in the hepatic region, which is stronger than that in the renal region; (ii)
gradual attenuation of far field echo; (iii) unclear display of intrahepatic lacuna
structure. However, only when fatty infiltration exceeds 30% can hepatic steatosis be
determined by ultrasonography. Other limitations of ultrasonography include its
equipment or operator-dependency and inability to distinguish steatohepatitis from
simple fatty liver.
5.2. TE examination
Liver stiffness and steatosis can be measured at the same time. Controlled attenuation
parameter (CAP), a highly sensitive, non-invasive method for the assessment of
steatosis based on TE, is able to detect steatosis as mild as 5%. CAP also features its
high specificity and stability. Furthermore, its diagnostic thresholds for hepatic
steatosis at different grades are free from disturbance of any other causes of chronic
liver diseases.51
For advanced ALD, thresholds of liver stiffness measurement (LSM)
for fibrosis and cirrhosis are 12.96 kPa and 22.7 kPa, respectively.52
TE monitoring is
of prognostic value as well.53,54
5.3. CT
Diffusely decreased liver density with the ratio of liver/spleen CT value of ≤1 is
adopted as the diagnostic standard: mild fatty liver, liver/spleen CT value ratio ≤1.0
but >0.7; moderate fatty liver, liver/spleen CT value ≤0.7 but >0.5; severe fatty liver,
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liver/spleen CT value ≤0.5.
5.4. MRI
Magnetic resonance spectroscopy (MRS), dual gradient-echo in-phase and
out-of-phase hepatic MRI are useful tools to quantitatively assess hepatic steatosis in
ALD. The threshold of magnetic resonance elastography (MRE) for the diagnosis of
hepatic fibrosis is 2.93 kPa, with a sensitivity of 98% and a specificity of 99%. MRE
can make a complete assessment of lesions in liver parenchyma that is unaffected by
obesity or ascites. The area under the receiver operating characteristic curve (AUROC)
of MRE for the staging of hepatic fibrosis (F2–F4) approximates 1. Shortcomings
should also be noted. Other causes that can result in increased hepatic stiffness, such
as inflammation, steatosis, congestion, cholestasis and portal hypertension, may
disturb fibrosis assessment by MRE. Besides, the high cost as well as the special
demand on equipment makes MRE less utilized than TE.55,56
Recommendation 2: Ultrasonography is currently the most commonly used
technique for the diagnosis of ALD, and can be adopted as the first choice in virtue of
its non-radioactive, non-invasive nature and low cost. However, ultrasonography
cannot sensitively identify fatty infiltration below 30%. Other limitations include
equipment or operator-dependency and inability to distinguish between simple fatty
liver and steatohepatitis. CT can make an overall assessment of liver and distinguish
liver cancer from local adipose deposition, yet CT examination is radioactive and can
hardly assess fibrosis. MRI, especially 1H magnetic resonance mass spectrometry, is
able to non-invasively, quantitatively assess liver fat content, though the high cost and
equipment-dependency confines its wide use. (A1)
Recommendation 3: As hepatic fibrosis is the most important factor that determines
the outcome of the disease, it is of vital significance to identify and quantify fibrosis
in order to make definite diagnosis, conduct follow-up visit and evaluate prognosis.
On limited resources, AST/PLT ratio is recommended as preliminary non-invasive
evaluation of hepatic fibrosis; on occasions when equipment and other economic
conditions are available, TE or FibroTest is recommended as the preferred
examination. (A1)
Recommendation 4: TE provides a rapid, simple, safe and widely adoptable way for
hepatic fibrosis assessment in ALD patients. However, hardly can it make accurate
determination regarding patients with ascites or morbid obesity. Its demand on
operating experience also hinders it from further promotion of application. In order to
correctly interpret TE, the following factors should be considered: interquartile range
(IQR)/median (<30%), serum transaminase level (<5 × upper limit of normal [ULN]),
body mass index (BMI) >30 kg/m2, usage of XL probe when skin–liver capsule
distance >25 mm, absence of extrahepatic cholestasis, no evidence of right heart
failure or liver congestion due to other causes, and exclusion of long-term excessive
alcohol consumption. (A1)
6. HISTOPATHOLOGICAL DIAGNOSIS OF ALD33
Major pathological changes of ALD are macro-vesicular hepatocyte fatty
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degeneration or a mixed type of macro-vesicular dominant with coexistent
micro-vesicular fatty degeneration. According to whether the diseased hepatic tissue
develops inflammation and fibrosis, ALD can be stratified into simple fatty liver,
alcoholic hepatitis, hepatic fibrosis and cirrhosis. A pathological diagnosis report of
ALD should cover such parameters as the severity of hepatic steatosis (F0–F3) and
inflammation (G0–G4) as well as the staging of hepatic fibrosis (S0–S4).
6.1. Simple fatty liver
Simple fatty liver can be stratified into three grades according to the proportion of
hepatocytes with fatty degeneration in the hepatic tissue specimen (F0–F3): F0,
presence of fatty degeneration in <5% of the hepatocytes; F1, presence of fatty
degeneration in ≥5% but <33% of the hepatocytes; F2, presence of fatty degeneration
in ≥33% but <66% of the hepatocytes; F3, presence of fatty degeneration in ≥66% of
the hepatocytes.
6.2. Alcoholic hepatitis and fibrosis
Severity of fatty degeneration in alcoholic hepatitis can also be stratified into three
grades (F0–F3), in accordance with that of simple fatty liver. In light of the severity of
inflammation, alcoholic hepatitis can be divided into four grades (G0–G4): G0, no
inflammation; G1, presence of a few balloon-shaped hepatocytes in acinar zone 3,
with sporadic isolated spotty acinar necrosis and peri-central vein inflammation; G2,
presence of apparent balloon-shaped hepatocytes in acinar zone 3, increased spotty
acinar necrosis, Mallory bodies and mild-to-moderate inflammation in portal area; G3,
extensive balloon-shaped hepatocytes in acinar zone 3, obvious spotty acinar necrosis,
presence of Mallory bodies and apoptotic bodies, moderate inflammation in portal or
peri-portal area or both; G4, confluent necrosis or bridging necrosis, or both.
According to the scope and pattern of fibrosis, hepatic fibrosis can be divided into
four grades (S0–S4): S0, no fibrosis; S1, focal or extensive peri-sinusoidal or
peri-cellular fibrosis in acinar zone 3 and peri-central fibrosis; S2, fibrosis extending
to portal area, peri-central sclerosing hyaline necrosis, focal or extensive
asterism-shaped fibrosis in portal area; S3, extensive acinar fibrosis, focal or
extensive bridging fibrosis; S4, cirrhosis.
Recommendation 5: A pathological diagnosis report of ALD should cover the
severity of hepatic steatosis (F0–F3) and inflammation (G0–G4) as well as the staging
of hepatic fibrosis (S0–S4). (C1)
6.3. Alcoholic cirrhosis
Hepatic lobular structure is completely destroyed, replaced by false lobules and
extensive fibrosis, which is defined as micronodular cirrhosis. Cirrhosis is described
as active or inactive based on the resence or absence of interface hepatitis at fibrous
septa.
7. MANAGEMENT OF ALD
7.1. Evaluation methods57–63
Many methods have been proposed and validated to evaluate the severity and
prognosis of ALD, including Child–Pugh classification, Maddrey’s discriminant
function (MDF), model for end-stage liver disease (MELD), Glasgow alcoholic
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hepatitis score (GAHS), age, bilirubin, international normalized ratio and creatinine
score (ABIC), Lille scoring system and TE. The MDF is calculated as 4.6 × increase
in PT (s) + TbIL (mg/dL), in which a score of over 32 suggests a high risk of 30-day
mortality. MELD score >18, GAHS >8, ABIC >9 can all be deemed as predictors of
poor prognosis. As for patients with severe alcoholic hepatitis, after a 7-day
corticosteroid therapy, efficacy of treatment can be evaluated by the Lille scoring
system, in which a score of >0.45 indicates steroid resistance.
7.2. Treatment
Therapeutic principles of ALD include discontinuation of alcohol consumption,
nutrition supplementation, alleviation of the severity of ALD, treatment of existing
secondary malnutrition and symptom-oriented treatment of alcoholic cirrhosis as well
as its complications.64–66
(i) Abstinence from alcohol
The cornerstone measurement is to ensure a thorough, immediate abstinence from
alcohol,67
which can help improve prognosis, histologically ameliorate liver injury,
reduce portal pressure, retard the progression of fibrosis and improve survival rates of
ALD patients at all stages. Those who have difficulty in quitting drinking proactively
could receive an oral baclofen therapy. Alcohol addicts should pay attention to
prevention and management of alcohol withdrawal syndrome, which can be treated
with tranquilizers.
(ii) Nutrition supplementation
Nutrition support is essential for ALD patients. A high-protein, low-fat diet on the
basis of abstinence is recommended; supplementation of vitamin B, vitamin C,
vitamin K and folic acid should be noted as well.68–70
The gap in protein intake should
be filled in patients with alcoholic cirrhosis. Patients with severe alcoholic hepatitis
are encouraged to take an extra meal at night (about 700 kcal/day) to prevent muscle
atrophy and increase skeletal muscle capacity. B-group vitamin supplementation
should be conducted in time for those presenting obvious symptoms of Wernickle’s
encephalopathy.
(iii) Pharmacological treatment
Corticosteroids can improve 28-day survival rates in patients with severe alcoholic
hepatitis,71
but fail to make significant improvement in 90-day or half-year survival
rates.72
Metadoxine can accelerate clearance of alcohol from the blood and thereby help
relieve alcohol poisoning, addiction and behavioral abnormalities,73–75
thus improving
survival76,77
.
S-adenosyl-L-methionine can improve clinical symptoms and serum biochemical
indices of ALD patients.78–80
Polyene phosphatidylcholine can prevent against
histological aggravation of ALD.81,82
Glycyrrhizic acid products, silymarin and
reduced glutathione, which play their anti-oxidative, anti-inflammatory, and
hepatocyte membrane or organelle protective roles on different degrees, can improve
liver biochemical indices according to some clinical trials.81,83–85
Bicyclol therapy can
also ameliorate alcoholic liver injury.86.87
In particular, in order to avoid further
burden on the liver and adverse reactions resulting from drug interactions,
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co-administration of multiple anti-inflammatory and liver protective drugs is not
recommended.
As ALD patients often present pathological changes of liver fibrosis, treatment against
fibrosis should be taken seriously. Up to now, some Chinese traditional herbal
medications have been available to treat hepatic fibrosis. Large-sample-sized,
randomized, double-blind, placebo-controlled clinical trials should be performed in
the future in accordance with evidence-based principles or histological examinations
to evaluate objectively the efficacy and safety of these drugs.
Management of ALD-related complications (e.g. esophagogastric variceal bleeding,
spontaneous bacterial peritonitis, hepatic encephalopathy, hepatocellular carcinoma)
should be actively conducted.67
Liver transplantation should be considered in patients with severe alcoholic cirrhosis,
which in the early stage can improve survival. Abstinence from alcohol for 3–6
months is required before transplantation as well as absence of severe alcohol-induced
injury of other organs.88,89
Recommendation 6: Abstinence from alcohol is the cornerstone of ALD
management. Nutrition supplementation is of vital importance. Treatment should be
tailored for each patient to decide whether and which kind of pharmacological
intervention should be adopted. (A1)
Recommendation 7: Hepatic inflammation and fibrosis may continue to exist after
abstinence. Pharmacological intervention should be adopted if there is evidence of
hepatic inflammation and fibrosis grading ≥F2. Though some anti-inflammatory, liver
protective drugs have been validated to be effective in animal models, strict
large-sample-sized clinical trials remain anticipated. There is yet no pharmacological
recommendation of definite curative effects for alcoholic hepatitis. (B1)
Recommendation 8: Active prevention and treatment of ALD-related complications
is recommended. For end-stage liver disease, liver transplantation may be considered
after abstinence from alcohol for 3–6 months. (B1)
LIST OF EXPERTS PARTICIPATING IN WRITING AND DISCUSSION OF
THE GUIDELINES (LISTED IN ALPHABETICAL ORDER BY PINYIN OF
LAST NAME):
Min Liang CHENG, Zhong Ping DUAN, Jian Gao FAN, Tao HAN, Fang Ping HE,
You Ming LI, Lun Gen LU, Xiao Lan LU, Yu Qiang MI, Yue Min NAN, Jun Qi NIU,
Chao SUN, Bing Yuan WANG, Hua WANG, Lai WEI, Cheng Fu XU, Ke Shu XU,
You Qing XU, Chao Hui YU, Ping Ge YUAN, Yu Tao ZHAN, Jing Min ZHAO, Bi
Hui ZHONG, Yue Yong ZHU, Hui ZHUANG, Zheng Sheng ZOU
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