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INTRODUCTION

  1. Top of page
  2. INTRODUCTION
  3. EPIDEMIOLOGY OF ALCOHOLIC LIVER DISEASE IN CHINA
  4. RISK FACTORS FOR ALCOHOLIC LIVER DISEASE
  5. CLINICAL DIAGNOSTIC CRITERIA OF ALCOHOLIC LIVER DISEASE
  6. IMAGING DIAGNOSIS OF FATTY LIVER
  7. HISTOPATHOLOGIC DIAGNOSIS OF ALCOHOLIC LIVER DISEASE
  8. MANAGEMENT OF ALCOHOLIC LIVER DISEASE
  9. REFERENCES

Alcoholic liver disease (ALD) encompasses a spectrum of hepatic injuries caused by long-term alcohol abuse. It is believed to progress from normal to simple steatosis (alcoholic fatty liver), then to steatohepatitis (alcoholic hepatitis) and finally to cirrhosis (when fibrogenesis predominates). Serious alcohol abuse may induce extensive hepatocyte necrosis and even acute liver failure. ALD is one of the most commonly encountered hepatic lesions in China and greatly jeopardizes public health. To further normalize the diagnosis and management of ALD, related domestic experts were invited by the Chinese National Workshop on Fatty Liver and Alcoholic Liver Disease on behalf of the Chinese Liver Disease Association to revise and update the Guidelines for management of alcoholic liver disease formulated in 2006, with reference to the latest results of domestic and overseas study and related diagnosis and treatment consensuses. This revision was performed mainly following the principle of evidence-based medicine, and the evidence upon which the recommendations given is graded into three classes and five levels1 and is indicated in the Roman numerals in brackets (Table 1).

Table 1.  Categorization of evidence bases
Evidence gradeDefinition
IRandomized control study
II-1Non-randomized control study
II-2Cohort or case-control study
II-3Serial studies at different times, with no controls
IIIOpinions and experiences of experts and authorities, epidemiological description

These guidelines are intended to assist clinicians in making correct decisions on the diagnosis and treatment of ALD rather than to serve as mandatory standards. In clinical practice, physicians should fully understand the optimal clinical evidence of the disease and the currently available medical resources to make a feasible therapeutic regimen in consideration of the individual patient's condition on the basis of their personal knowledge and experience.

EPIDEMIOLOGY OF ALCOHOLIC LIVER DISEASE IN CHINA

  1. Top of page
  2. INTRODUCTION
  3. EPIDEMIOLOGY OF ALCOHOLIC LIVER DISEASE IN CHINA
  4. RISK FACTORS FOR ALCOHOLIC LIVER DISEASE
  5. CLINICAL DIAGNOSTIC CRITERIA OF ALCOHOLIC LIVER DISEASE
  6. IMAGING DIAGNOSIS OF FATTY LIVER
  7. HISTOPATHOLOGIC DIAGNOSIS OF ALCOHOLIC LIVER DISEASE
  8. MANAGEMENT OF ALCOHOLIC LIVER DISEASE
  9. REFERENCES

Data on nationwide large-scale epidemiological investigations of ALD in China are unavailable, but regional epidemiological studies indicate a rising trend in the drinking population and in the prevalence of ALD. An epidemiological investigation in northern China showed that the proportion of alcoholics among adults in the general population had increased from 0.21 to 14.3% from the early 1980s to the early 1990s.2 Epidemiological investigations conducted in the southern and middle-western provinces at the beginning of present century revealed that the percentage of people with a drinking habit in the general population had increased to 30.9–43.4% (III).2–5

Many alcoholics and people with an excessive alcohol intake in the drinking population have demonstrated related health problems, of which ALD is the most frequently seen alcohol-induced organ injury. Epidemiological investigations carried out in southern and middle-western provinces at the beginning of the present century demonstrated that the prevalence of ALD in adults was 4.3–6.5% (III).3–5 The prevalence of ALD in hospitalized patients with liver diseases increased from 4.2% in 1991 to 21.3% in 1996, and the etiology constituent ratio of alcohol abuse in patients with cirrhosis rose from 10.8% in 1999 to 24.0% in 2003 (III).6,7 Alcohol-induced liver injury has become an important issue that cannot be neglected in China.

RISK FACTORS FOR ALCOHOLIC LIVER DISEASE

  1. Top of page
  2. INTRODUCTION
  3. EPIDEMIOLOGY OF ALCOHOLIC LIVER DISEASE IN CHINA
  4. RISK FACTORS FOR ALCOHOLIC LIVER DISEASE
  5. CLINICAL DIAGNOSTIC CRITERIA OF ALCOHOLIC LIVER DISEASE
  6. IMAGING DIAGNOSIS OF FATTY LIVER
  7. HISTOPATHOLOGIC DIAGNOSIS OF ALCOHOLIC LIVER DISEASE
  8. MANAGEMENT OF ALCOHOLIC LIVER DISEASE
  9. REFERENCES

A number of risk factors have been identified that influence the progression or aggravation of alcoholic liver injury. Risk factors of ALD that have been identified in domestic and overseas studies mainly include accumulated alcohol consumption, years of drinking, type of alcoholic beverages consumed, pattern of drinking, female gender, nutritional status, obesity, concomitant viral hepatitis, exposure to drugs or toxins, ethnicity, genetic factors and more.

Findings of epidemiological investigations indicate that once a threshold level of alcohol consumption is exceeded, the risk of hepatotoxicity increases dramatically; namely, the risk of liver injury is significantly increased when a certain alcohol intake with a certain number of years of drinking is attained (III).8 However, because of individual variation, the dose-response correlation between alcohol consumption and liver injury is not so definite (III).8–10

A great many types of alcoholic beverages are available today. Different types of alcoholic beverages may associate with different liver impairments (III).11,12 The pattern of drinking is also a risk factor of liver injury. Drinking while fasting is more likely to lead to liver injury than drinking with meals (III).12 Women have been found to be more sensitive to alcohol-mediated hepatotoxicity and may develop more severe ALD with lower alcohol consumption and shorter durations of drinking than men (III).13 Blood alcohol levels in women differ significantly from those in men after the consumption of equal amount of alcohol (II-2).14

Race,15 (II-2), heredity16,17 (III) and individual variation8 (III) are also important risk factors for ALD. The allele frequency and genotype distribution of ALD-predisposing genes, such as alcohol dehydrogenase (ADH) 2, ADH3 and acetaldehyde dehydrogenase (ALDH) 2 in the Han population differ from that of peoples in developed countries. This may be one of the reasons why the incidence of ALD in China is lower than that in developed countries.16 Not all alcohol abusers will develop ALD; only a small proportion is affected, indicating the presence of individual variation in a population in the same region.8

The increase in the mortality rate of ALD is related to the degree of malnutrition in the patient (III).18 A vitamin A deficiency or a decrease of the level of vitamin E may aggravate liver injury (III).19 Diets rich in polyunsaturated fatty acids could facilitate the progression of ALD, whereas saturated fatty acids have a protective effect against ALD (III).20 Obesity or overweight may increase the risk of ALD progression (III).8

A synergistic harmful effect on liver has been observed between hepatitis virus infection and alcohol consumption (III).21 Drinking alcohol while infected with a hepatitis virus or hepatitis virus infected in the presence of ALD will trigger the development and progression of liver diseases.

CLINICAL DIAGNOSTIC CRITERIA OF ALCOHOLIC LIVER DISEASE

  1. Top of page
  2. INTRODUCTION
  3. EPIDEMIOLOGY OF ALCOHOLIC LIVER DISEASE IN CHINA
  4. RISK FACTORS FOR ALCOHOLIC LIVER DISEASE
  5. CLINICAL DIAGNOSTIC CRITERIA OF ALCOHOLIC LIVER DISEASE
  6. IMAGING DIAGNOSIS OF FATTY LIVER
  7. HISTOPATHOLOGIC DIAGNOSIS OF ALCOHOLIC LIVER DISEASE
  8. MANAGEMENT OF ALCOHOLIC LIVER DISEASE
  9. REFERENCES

Alcoholic liver disease can be diagnosed if criteria 1, 2, 3 and 5 or criteria 1, 2, 4 and 5 are met and may be suspected if only criteria 1, 2 and 5 are satisfied.22 ALD with viral hepatitis can be diagnosed if criterion 1 is met and evidence of current infection of hepatitis virus is available.

  • 1
    The patient should have a long-term habitual alcohol consumption, usually longer than 5 years, with a converted alcohol intake ≥ 40 g/d (male) or ≥20 g/d (female), or a confirmed history of significant alcohol consumption within the past 2 weeks with a converted alcohol intake > 80 g/d (III).22 Influencing factors such as gender, genetic predisposition and so on should be taken into consideration. The conversion formula of alcohol intake is: alcohol intake (g) = wine or liquor consumed (mL) × alcohol content (%) × 0.8.
  • 2
    Symptoms and signs of ALD are non-specific and variable, ranging from complete absence of symptoms to florid features of liver failure and portal hypertension. Patients can have one or more of the following symptoms or signs: right upper quadrant pain or fullness, fever, weakness, anorexia, nausea and vomiting, malaise, confusion, sleep-wake cycle alteration, hepatomegaly, splenomegaly, cachexia, jaundice, spider telangiectasia and so on (III).22
  • 3
    Laboratory abnormalities in ALD mainly include the elevation of aspartate aminotransferase (AST) (II-2), alanine aminotransferase (ALT) (III), γ-glutamyl transferase (GGT) (II-2), total bilirubin (TBil) (III), prothrombin time (III), mean corpuscular volume (MCV) (II-2) and carbohydrate deficient transferrin (CDT) (II-2).22–25 An AST/ALT ratio > 2 and an increase of GGT and MCV are characteristics of ALD, whereas CDT, though specific, has not yet been tested clinically as a routine. These indices could decrease markedly after alcohol withdrawal and usually return to essentially normal levels within 4 weeks (GGT normalizes slowly) (II), which may facilitate the diagnosis.26,27
  • 4
    Typical manifestations of fatty liver and cirrhosis are present in images by some non-invasive imaging techniques (see section of imaging diagnosis) (II-2).28–31
  • 5
    Exclusion of other conditions that have similar features, including nonalcoholic steatohepatitis, chronic viral hepatitis, Wilson disease, drug-induced and toxic liver injury, primary biliary cirrhosis and autoimmune liver diseases (III).22

The clinical classification of cases complying with ALD diagnostic criteria is as follows:

  • 1
    Mild alcohol-induced liver injury: liver biochemical tests, imaging and histopathological examinations are nearly normal or only slightly abnormal.
  • 2
    Alcoholic fatty liver: imaging results meet the criteria for diffuse fatty liver, with or without minor serum aminotransferase elevation (typically less than twice the upper limit of normal) and GGT elevations.
  • 3
    Alcoholic hepatitis: the diagnosis of alcoholic hepatitis is based on a thorough history, physical examination and review of laboratory tests. Characteristically, the AST/ALT ratio exceeds 2 and the absolute aminotransferase level does not exceed 300 U/L unless a superimposed hepatic insult exists. Other common and nonspecific laboratory abnormalities include anemia and leukocytosis. Patients with alcoholic hepatitis usually complain of fatigue, anorexia and weight loss. There is tender hepatomegaly and usually pyrexia. Severe cases are marked by manifestations of liver failure and reversible portal hypertension such as repeated vomiting, jaundice, ascites, encephalopathy and a bleeding diathesis.
  • 4
    Alcoholic cirrhosis: the diagnosis of alcoholic cirrhosis rests on the classic clinical, laboratory and imaging findings of this end-stage liver disease in a patient with a history of significant alcohol intake.

IMAGING DIAGNOSIS OF FATTY LIVER

  1. Top of page
  2. INTRODUCTION
  3. EPIDEMIOLOGY OF ALCOHOLIC LIVER DISEASE IN CHINA
  4. RISK FACTORS FOR ALCOHOLIC LIVER DISEASE
  5. CLINICAL DIAGNOSTIC CRITERIA OF ALCOHOLIC LIVER DISEASE
  6. IMAGING DIAGNOSIS OF FATTY LIVER
  7. HISTOPATHOLOGIC DIAGNOSIS OF ALCOHOLIC LIVER DISEASE
  8. MANAGEMENT OF ALCOHOLIC LIVER DISEASE
  9. REFERENCES

Imaging techniques could be taken to observe the distribution pattern of fatty infiltration of the liver, roughly determining the severity of diffuse fatty liver and checking the development of cirrhosis and hepatocellular carcinoma.28–31 However, routine hepatic imaging cannot distinguish simple steatosis and steatohepatitis, and cannot detect mild degree steatosis or fibrosis. It should be noted that diffuse liver echo enhancement in ultrasonography and reduction of density in computed tomography (CT) may also be present in other chronic liver diseases.

Ultrasonic imaging diagnosis

Diffuse fatty liver can be diagnosed if two of the following three abdominal ultrasound manifestations are present: (i) diffuse echo enhancement in the liver near field, echoes being more intensive than that in the kidney field; (ii) gradual echo attenuation in the liver far field; and (iii) a blurred display of intrahepatic ductal structures.

CT diagnosis

A steatotic liver is low in density when compared with the spleen and paraspinal muscle on non-contrast CT images, with a liver: spleen CT ratio ≤ 1. Among them, a mild degree of fatty liver has a liver: spleen CT ratio less than 1 but more than 0.7, a moderate degree liver: spleen CT ratio less than or equal to 0.7 but more than 0.5, and a severe degree has liver: spleen CT ratio less than or equal to 0.5.

HISTOPATHOLOGIC DIAGNOSIS OF ALCOHOLIC LIVER DISEASE

  1. Top of page
  2. INTRODUCTION
  3. EPIDEMIOLOGY OF ALCOHOLIC LIVER DISEASE IN CHINA
  4. RISK FACTORS FOR ALCOHOLIC LIVER DISEASE
  5. CLINICAL DIAGNOSTIC CRITERIA OF ALCOHOLIC LIVER DISEASE
  6. IMAGING DIAGNOSIS OF FATTY LIVER
  7. HISTOPATHOLOGIC DIAGNOSIS OF ALCOHOLIC LIVER DISEASE
  8. MANAGEMENT OF ALCOHOLIC LIVER DISEASE
  9. REFERENCES

The primary pathological change in ALD is macro-vesicular hepatocyte fatty degeneration or mixed-vesicular hepatocyte fatty degeneration (macro-vesicular and micro-vesicular fatty degeneration, with the former type accounting for most cases). Based on whether the diseased hepatic tissue develops inflammation and fibrosis, ALD is classified into simple fatty liver, alcoholic hepatitis, hepatic fibrosis and cirrhosis. A pathological diagnosis report of ALD should cover the steatosis severity (F0–4), inflammation severity (G0–4) and hepatic fibrosis grading (S0–4).22

Alcoholic fatty liver

The simple fatty liver is divided into four grades according to the proportion of hepatocytes with fatty degeneration in the hepatic tissue slice and the occupation of hepatocyte fatty degeneration in the hepatic tissue specimen, (F0–4): F0, presence of fatty degeneration in < 5% of the hepatocytes; F1, presence of fatty degeneration in 5%–30% of the hepatocytes; F2, presence of fatty degeneration in 31%–50% of the hepatocytes; F3, presence of fatty degeneration in 51%–75% of the hepatocytes; F4, presence of fatty degeneration in more than 75% of the hepatocytes.

Alcoholic hepatitis and hepatic fibrosis

The severity of fatty degeneration in alcoholic hepatitis, similar to simple fatty liver, is also divided into four grades (F0–4). Based on the severity of inflammation, alcoholic hepatitis is divided into four grades (G0–4): G0, no inflammation; G1, presence of a few balloon-shaped hepatocytes in acinar zone 3 and sporadic isolated spotty acinar necrosis and peri-central vein inflammation; G2, presence of apparent balloon-shaped hepatocytes in acinar zone 3, more spotty acinar necrosis, Mallory bodies and mild to moderate inflammation of the portal area; G3, extensive balloon-shaped hepatocytes in acinar zone 3, pronounced spotty acinar necrosis, presence of Mallory bodies and apoptotic bodies, moderate inflammation of portal area or periportal inflammation, or both; G4, confluent necrosis or bridging necrosis, or both.

By the scope and pattern of fibrosis, hepatic fibrosis is divided into four grades (S0–4): S0, no fibrosis; S1, focal or extensive perisinusoidal or pericellular fibrosis in acinar zone 3 and peri-central vein fibrosis; S2, fibrosis expanding to portal area, peri-central vein sclerosing hyaline necrosis, focal or extensive asterism-shaped fibrosis of portal area; S3, extensive fibrosis of acinar, focal or extensive bridging fibrosis; S4, cirrhosis.

Alcoholic cirrhosis

Hepatic lobular structure is completely destroyed and replaced by false lobulation and extensive fibrosis, and the gross pathology is defined as micronodular cirrhosis. Cirrhosis is described as active or inactive by the presence or absence of interface hepatitis at fibrous septa.

MANAGEMENT OF ALCOHOLIC LIVER DISEASE

  1. Top of page
  2. INTRODUCTION
  3. EPIDEMIOLOGY OF ALCOHOLIC LIVER DISEASE IN CHINA
  4. RISK FACTORS FOR ALCOHOLIC LIVER DISEASE
  5. CLINICAL DIAGNOSTIC CRITERIA OF ALCOHOLIC LIVER DISEASE
  6. IMAGING DIAGNOSIS OF FATTY LIVER
  7. HISTOPATHOLOGIC DIAGNOSIS OF ALCOHOLIC LIVER DISEASE
  8. MANAGEMENT OF ALCOHOLIC LIVER DISEASE
  9. REFERENCES

Prognosis evaluation

Many methods have been used for evaluating the severity and prognosis of patients with alcoholic hepatitis and cirrhosis, including Child-Pugh classification, Maddrey's discriminant function (MDF), and the model for end-stage liver disease (MELD) scoring. The MDF is of greater value in stratifying the severity of alcoholic hepatitis.32–34 MDF = (4.6 × increase in prothrombin time (sec)] + serum bilirubin (mg/dL). Patients with a score greater than or equal to 32 are at the highest risk of dying and with a 1-month mortality as high as 30-50%.32–34

Treatment of alcoholic liver disease

The therapeutic principle of ALD includes discontinuation of alcohol consumption, nutritional supplementation, treatment of extrahepatic complications of alcoholism and management of severe hepatitis and advanced cirrhosis.35,36

  • 1
    Abstinence from alcohol: the most important measure is to ensure a total and immediate abstinence from alcohol (I).37 The prevention and management of withdrawal syndrome should be closely monitored during alcohol withdrawal.
  • 2
    Nutritional support: good nutritional support is essential for all patients with malnutrition. Nutritional deficiencies should be sought and treated aggressively. A high-protein, high-calorie and low-fat diet should be encouraged for ALD patients; in addition, the supplementation of vitamin B, vitamin C, vitamin K and folic acid should be initiated early on (II-2).38
  • 3
    Medical therapy of alcoholic hepatitis: (i) corticosteroids: prednisolone (40 mg/day for 4 weeks then tapered over a 2–4 week) can increase the 1-month survival rate of patients with severe alcoholic hepatitis. Corticosteroids should thus be used in patients with a definite diagnosis of severe alcoholic hepatitis with the MDF score > 32, hepatic encephalopathy, or both (I).39,40 (ii) Metadoxine can accelerate the clearance of alcohol from the blood and thereby facilitate the improvement of alcoholism symptom and behavioural abnormalities (I).41 (iii) S-adenosyl-L-methionine can improve the symptoms and biochemical indices of ALD patients (I).42,43 Polyene phosphatidylcholine can prevent the histological aggravation of ALD (I).44,45 Glycyrrhizic acid products, silymarin, polyene phosphatidylcholine and reduced glutathione have various degrees of anti-oxidative, anti-inflammatory and hepatocyte membrane protective efficacy and can improve liver biochemical tests in some clinical trials (II-2, II-3).44,46,47 Bicyclol therapy can also alleviate the symptoms of ALD (II-2).48 However, the co-administration of multiple anti-inflammatory and liver protective drugs is not recommended, to avoid the increase of liver burden and prevent adverse reactions originating from drug interactions (III). ALD patients often demonstrate pathological changes of liver fibrosis, therefore therapy against fibrosis should be seriously considered (III). Certain traditional Chinese medicines against hepatic fibrosis are available in China. Large sample sized, double-blind, randomized, placebo-controlled clinical trials should be performed in accordance with evidence-based principle and with histology results to evaluate objectively the efficacy and safety of these drugs.
  • 4
    Management of complications of ALD: in patients with severe hepatitis and cirrhosis, management should be focused on the treatment of hepatic complications (e.g., portal hypertension, esophageal or fundus varices, spontaneous bacterial peritonitis, hepatic encephalopathy and bleeding due to portal hypertension) and screening for hepatocellular carcinomas (III).37 Liver transplantation should be considered in patients with severe alcoholic hepatitis and decompensated cirrhosis, and the patient should abstain from alcohol for at least 3-6 months before the operation and should have no severe alcoholic injury to other organs (II-2).49

REFERENCES

  1. Top of page
  2. INTRODUCTION
  3. EPIDEMIOLOGY OF ALCOHOLIC LIVER DISEASE IN CHINA
  4. RISK FACTORS FOR ALCOHOLIC LIVER DISEASE
  5. CLINICAL DIAGNOSTIC CRITERIA OF ALCOHOLIC LIVER DISEASE
  6. IMAGING DIAGNOSIS OF FATTY LIVER
  7. HISTOPATHOLOGIC DIAGNOSIS OF ALCOHOLIC LIVER DISEASE
  8. MANAGEMENT OF ALCOHOLIC LIVER DISEASE
  9. REFERENCES