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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/

mailto:[email protected]

wuyingying

英文



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





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





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.





(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,





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





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





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,





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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