In a cross-sectional survey from Shandong province, the ALD incidence increased with age until 50 years, and most ALD patients were 40-49 years old[9]. The 2017 Annals of Chinese Health and Family Planning showed the constituent ratio of ALD patients aged between 15 to 44 years old who were discharged from hospitals, and the percentages significantly increased from 20% among 45-59 year olds to 48.8% among 60 year olds and 31.2% among those > 60 years old.

In addition, a meta-analysis of adolescents found that the percentages of drinkers were highest among vocational high school students (44.7% for males, 28.8% for females). Alcohol consumption rates in high school students were higher (36.5% for males, 21.2% for females) than those in middle school students (23.6% for males and 15.3% for females). The percentages of drinkers among males were significantly higher in all three types of schools compared with those among females[31]. Although prevalence estimates among Chinese students were generally lower than those reported in Western countries, an increasing trend has been observed in recent decades[32].

Excessive alcohol consumption, especially of distilled alcoholic beverages containing high levels of alcohol (spirit or liquor), usually occurs in circumstances of formal social activities. In anticipation of establishing, maintaining, and/or developing personal or social networking relationships, peer pressure to consume an excessive amount of alcohol exists among participants in social events, such as dinners or banquets among middle-aged business clients or partners. Middle-aged people represent the main population involved in these social activities. Moreover, as they are more likely to have a relatively stable family income and independent financial status, middle-aged people in China have more accessibility to alcoholic beverages.

In China, the proportion of males who report high alcohol consumption is higher than that of females. Chinese males typically have more social opportunities to drink than females, and a common opinion in these settings is that males who have the ability to drink large volumes are perceived as masculine. In contrast, the traditional responsibility of Chinese adult females is to manage the daily life of their families, which keeps women in these roles busy caring for children and elderly relatives. They do not have as many opportunities to participate in social engagements as males do. Thus, the delegation of family responsibility restricts the females from frequently consuming alcohol. However, as more women are pursuing professional careers, more adult women are maintaining bachelorette status, and drinking among women is no longer viewed as exceptional by Chinese society. A continued increase in the percentage of female drinkers is expected over time. According to the Global status report on alcohol and health 2018, in absolute numbers there were about 91000 more women who drank alcohol in 2016 than in 2000 despite a 5% decrease in the current worldwide drinking prevalence from 37.3% to 32.3%[7]. The prevalence rates of current drinking among women in the World Health Organization Western Pacific Region were 39.3%, 36.4%, 42.0%, and 40.7% in 2000, 2005, 2010, and 2016, respectively. In China specifically, the total, including recorded and unrecorded, per capita alcohol consumption for women was 2.2 (95%CI: 1.9-2.5) and 2.5 (95%CI: 2.4-2.6) in 2014 and 2018, respectively[7,33]. However, the age-standardized death rates for liver cirrhosis in females were 5.8 and 8.3 per 100000 population (15+) in 2012 and 2016, while the alcohol-attributable fractions were 59.8% and 41.6% in 2012 and 2016, respectively[7,33]. Women are known to express lower levels of alcohol dehydrogenase (ADH) in hepatocytes and to have different ratios of total body water and fat compared with men. Thus, compared with men, they are less tolerable of alcohol, tend to develop ALD after exposure to lower amounts of alcohol, and are more vulnerable to ALD progression[34].

In China, spirits make up about 70% of the alcoholic beverages consumed, and it is estimated that up to 25% of the consumed alcohol is not registered[35]. Homemade wines including rice wines, which are not subject to taxation, are distilled by farmers in their family workshops. A cross-sectional survey[36] found that the three most commonly consumed alcoholic beverages in rural regions in Hunan province were homemade alcoholic beverages, beer, and high-alcohol liquors. In Henan, they were beer, high and low alcohol liquors. Traditional distilled spirits (bai jiu) are the most popular unrecorded alcohols, and the production volume is often underestimated by official statistics. It is of importance to include home brews in the drinking surveys in both China and other countries[36,37]. The main concern regarding homemade alcoholic beverages is the easy access to high alcohol drinking at an exceedingly affordable price. Furthermore, Newman et al[35] commented that the major health risks posed by unrecorded Chinese bai jiu include not only the high concentration of alcohol but also the presence of toxic impurities including heavy metals and acetaldehyde.

Although the pathogenesis of ALD is complex and remains unclear, the oxidative metabolites of alcohol, including acetaldehyde and ROS, are the main culprits for ALD. Acetaldehyde is reactive with DNA and proteins and may form adducts, which act as neoantigens that elicit an immune response and contribute to liver injury. Acetaldehyde also interferes with DNA synthesis, methylation, and repair, facilitating HCC susceptibility.

There are two major enzyme systems that metabolize EtOH into acetaldehyde (AA) via oxidative degradation. Members of the ADH family in hepatocytes are the enzymes responsible for metabolizing ingested alcohol. ADH activity determines alcohol tolerance and ALD susceptibility. Mutations in ADH genes have been linked to both protection from and susceptibility to ALD. As examples, due to slower oxidation rates, the ADH2*1, ADH3*2, and ALDH2*2 alleles are associated with high blood acetaldehyde concentrations, which correspond to a greater risk of adverse effects, and thus, may serve to reduce alcohol consumption and the risk of related diseases. By contrast, certain genetic variants involving ADH2*2, ADH3*1, ALDH2*1, and CYP2E1*1 allow a higher oxidation rate, which corresponds to an increased alcohol clearance rate, facilitating the consumption of more alcohol and increasing the risk of alcohol-related diseases[38-40]. Clearly, ADH activity is affected by genetic polymorphisms of the ADH genes. Several studies from Taiwan and mainland China identified genetic polymorphisms in ADH2, ADH3, and ALDH2 genes among the Chinese Han population, and they are different from those reported in the Caucasian population. Such variation in ADH genes may lead to differences in the susceptibilities to ALD between the Chinese Han population and Caucasians[41-43]. Our previous research showed that ALDH2 deficiency is accompanied by higher levels of serum acetaldehyde and corticosterone after alcohol consumption, leading to the attenuation of T-cell activation and concanavalin A-induced T-cell hepatitis in both mice and humans[40]. ALDH2-deficient individuals may have an elevated risk for alcohol-related cancers and diseases due to T-cell suppression[40]. We investigated ALDH2 polymorphisms in two cohorts, one consisting of 450 alcoholic cirrhosis patients and the other consisting of 683 patients with HBV-related liver diseases, and found that the occurrence of HBV-related cirrhosis and HCC among alcohol drinkers with HBV infection was linked to polymorphism of the ALDH2*1/*2 genes, which was also a risk factor for progression of cirrhosis to HCC and of HCC stage B to stage C or D. Less than 5% of patients with alcoholic cirrhosis were found to have the ALDH2*1/*2 genotype, and none had the ALDH2*2/*2 genotype. In addition, polymorphism in the PsaI/Psat restriction site of the CYP2E1 gene was also linked to ALD susceptibility[44]. Finally, polymorphism in the patatin-like phospholipase domain-containing protein 3 (PNPLA3) gene may predispose ALD patients to more severe alcohol-related liver injury[45]. Recently, a large case-control multicenter study conducted in China showed that both the allele and genotype frequencies of rs738409 in the PNPLA3 gene were significantly associated with ALD (P = 6.25 × 10^-14 and P = 9.05 × 10^-13)[46]. In addition, a polymorphism in the silent mating type information regulation 2 homolog 1 (SIRT1) gene was associated with alcoholic fatty liver disease (AFLD) in the Han population[47].

On the other hand, chronic alcohol consumption up-regulates cytochrome P450 2E1 (CYP2E1) gene expression in response to the need to convert alcohol to acetaldehyde. This CYP2E1-dependent microsomal ethanol oxidizing system (MEOS) generates more ROS[48]. Hepatocytes injured after alcohol intake release endogenous DAMPs. DAMPs can activate Toll-like receptor 4 (TLR4) on Kupffer cells to promote the secretion of proinflammatory cytokines such as interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) and to activate the inflammasome[49]. The activated Kupffer cells also secrete CXC chemokines to attract infiltrating neutrophils and other mononuclear cells, which may aggravate hepatic necroinflammation[50].

Factors of socioeconomic status, including education, marital status, occupation, and family income, have also been linked to ALD. Individuals with a low level of education, a lack of immediate family, a high-stress job, or a low income are more susceptible to alcoholism, and the incidence of ALD is higher in these groups. Such a linkage was also reported by studies in the United States[9,51]. Single individuals tend to be financially better off, participate in more social engagements, and have more opportunities for drinking compared with married persons. Also, individuals who perform hard manual labor daily in rural areas tend to consume more alcohol, often at pubs after work[9].

Adipose tissue, which is an important source of proinflammatory cytokines (such as TNF-α), may facilitate ALD development and progression[52]. Both elevated BMI and visceral fat accumulation are independent risk factors for alcoholic hepatitis in ALD[53]. A study showed that the BMI was significantly higher in an ALD group than in a non-ALD group[54]. Additionally, chronic heavy alcohol consumption, obesity, and viral infections share the same steatosis pathology[55]. Data from the China Health and Nutrition Survey collected in 1997, 2000, 2004, 2006, 2009, and 2011 showed an increasing trend in the BMI of Chinese adults, with that of males increasing by 0.21 kg/m² per year and that of women increasing by 0.16 kg/m² per year[56].

A combination of excessive alcohol consumption and endemic chronic HBV/HCV infection may promote advancement of chronic liver diseases, regardless of the initial etiology, and increase the ALD and chronic HBV infection (CHB) burden in China[57]. Alcohol consumption by chronic HBV- or chronic HCV-infected patients is an additional risk factor for accelerated progression of chronic hepatitis to liver cirrhosis, HCC, or liver-related mortality[57,58]. Moreover, alcohol consumption may thus enable HCV evasion from the immune response and facilitate HCV replication[57]. Further studies should be directed at exploring the impact of ALD on the long-term outcomes of antiviral therapy.

A population-based study of Asian patients with chronic liver disease in the United States from 2007 to 2016 found that chronic HBV infection in different Asian populations ranged from 9%-25% in contrast to 0.5% in the general United States population[18]. A nationwide serologic survey of HBV infection in China showed that HBV surface antigen (HBsAg) positivity rates in individuals aged 1-4, 5-14, and 15-29 years were 0.3%, 0.9%, and 4.4%, respectively, in 2014, and these percentages were far lower than the average of 9.8% in 1992 due to the introduction of universal HBV vaccination[59]. The prevalence of ten HBV genotypes (A-J) varies among different parts of the world: genotypes A and D are the most prevalent in Africa and Europe, and genotypes B and C are dominant in Asia and Oceania[60,61]. In addition, age-standardized HCV-related mortality was lower in the all United States Asian population throughout the study period[18]. However, 70% of HCV-infected patients in the European and North American countries were heavy alcohol drinkers, and 30%-40% of ALD cases had concomitant chronic HCV infection. These two concurrent diseases may exert synergistic effects on hepatic necroinflammation, tumorigenesis, and oxidative stress[62]. The fact that hepatitis C-related chronic liver disease is expected to decline over time highlights the need to improve the treatment of ALD, which may soon rank as the number one cause of cirrhosis as the frequencies of ALD cases continue to rise in European and North American countries[63]. HCV infection in China has showed a steady decrease from an average 3.2% in 1992 to 0.36% in 2010[64]. HCV genotypes 1b and 2a are predominant in China, whereas HCV genotypes 1 and 3 account for most HCV infections in Europe[65].

Abstinence from alcohol is the most effective approach to mitigating or ceasing alcohol-related liver injury. International guidelines from China, the United States, and Europe, as well as questionnaires including the Alcohol Use Disorders Identification Test (AUDIT), the Michigan Alcoholism Screening Test (MAST), and the CAGE alcohol screening questionnaire, emphasize the discrimination of alcohol dependence or abuse[66-68]. Moreover, despite progress in drug-based ALD treatments, ALD therapeutics remain insufficient[69]. Currently, only a few drugs are approved for ALD treatment, including acamprosate, disulfiram, naltrexone, and nalmefene, and not all of them are available in every country[63]. A main focus of clinical research is rectifying alcohol use disorder (AUD) in ALD patients. Currently, a combination of drug therapy, psychosocial interventions, and medical management is recommended. Nonpharmacological treatment consists of cognitive behavioral therapy, outpatient motivational consultation, and attendance at Alcoholics Anonymous meetings. If patients develop psychological problems, fail to improve with outpatient therapy, and live in an unstable family, in-patient therapy is highly advised. Drug-based therapy for AUD is also available. Attention should focus on the prevention of withdrawal syndrome during abstinence. In addition, sufficient nutritional supplementation of vitamin B, C, D, E, and K, and folate should be provided to ALD patients[70]. Vitamin D deficiency was suggested to promote liver fibrosis and/or inflammation, particularly during chronic HCV infection[71]. A high-protein and low-fat diet is suggested for patients with alcoholic cirrhosis. A suggested energy supply of 35-40 kcal/kg body weight (BW) per day (147-168 kJ/kg BW per day) and a protein intake of 1.2-1.5 g/kg BW per day are recommended by the European Society for Clinical Nutrition and Metabolism guidelines[72].

Although abstinence is advised, not all patients can maintain sobriety. Thus, some patients may require drug-based treatment. Treatment with corticosteroids (CS) may increase the survival rate of patients with SAH. However, patients who have a Lille score of ≥ 0.45 may not benefit from continued administration of CS. The antioxidants metadoxine and N-acetylcysteine (NAC) have also been suggested for treatment of ALD. Metadoxine accelerates the clearance of alcohol from the serum and improves alcoholic symptoms and abnormal behavior[73]. NAC replenishes the glutathione level in hepatocytes, reduces free radicals, and inhibits the expression of nuclear factor κB and TNF-α. NAC can also prevent alcohol addiction and reduce alcohol consumption[74]. Additional drugs can be used to treat ALD, including S-adenosyl-L-methionine (SAMe), polyene phosphatidylcholine, glycyrrhizic acid products, silymarin, polyene phosphatidylcholine, reduced glutathione, and bicyclol therapy. SAMe, a precursor of glutathione and a major methyl donor for methyltransferase reactions, was shown to improve the symptoms and biochemical parameters of ALD[75]. Polyene phosphatidylcholine can prevent histological aggravation in ALD patients[76]. The glycyrrhizic acid products silymarin, polyene phosphatidylcholine, and reduced glutathione share antioxidation and anti-inflammation effects and to some extent protect cellular membranes and organelles, improving liver biochemical indices[77]. Bicyclol therapy can also alleviate the ALD symptoms[78].

Many ALD patients in China, especially those who fail to respond to treatment with small molecule drugs, pursue traditional Chinese medicine (TCM) as an adjunct or alternative therapy. Several TCM formulae are known to be effective at mitigating hepatic fibrosis. Several herbal medicines, including Cnidium monnieri (L.) Cusson (Apiaceae), and Curcuma longa L. (Zingiberaceae), have been used for ALD treatment in China[79]. Gao et al[80] suggested that ginsenoside Rg1 is a potential hepatoprotective agent that functions through glucocorticoid receptor (GR) and the GR-related nuclear factor-κB pathway. Wu et al[81] suggested that a TCM formula of Qinggan Huoxue can effectively alleviate the ALD pathology in rats through the lipopolysaccharide-Kupffer cell signaling pathway. Because TCM formulae consist of multiple components with complex chemistry and pharmacology characteristics, they could be made more effective once the active components and their underlying mechanisms are clearly elucidated. The potential side effects of TCM must be evaluated through large-sample, randomized, double-blind clinical trials that are consistent with the principles of evidence-based medicine.

For ALD patients who cannot tolerate steroid drugs, new therapies are being evaluated in clinical trials, including therapies based on human induced pluripotent stem cells, bovine colostrum and hyperimmune bovine colostrum (ClinicalTrials.gov NCT02265328; NCT02473341; NCT01968382), fecal microbiota transplantation (ClinicalTrials.gov NCT03091010; NCT02458079), and granulocytapheresis.

LT is a curative therapy for patients with severe alcoholic liver cirrhosis. The indications for LT in China include HBV-related HCC; HBV-, HCV-, or alcohol-related cirrhosis; and biliary atresia in children. The 2011 edition of the China Liver Transplant Annual Scientific Report prepared by the China Liver Transplant Registry (CLTR) reported 561 cases of LT for ALD, which accounted for 2.77% of all LT cases. The number of patients with end-stage ALD who have received LT in recent years in mainland China has been increasing[82]. Before orthotopic LT, a 3-6-mo period of alcohol abstinence is required as outlined by the 2018 Guidelines for Management of Alcoholic Liver Disease, whereas a similar requirement has been removed from the ACG Clinical Guidelines and EASL Clinical Practical Guidelines[66-68]. A recent retrospective analysis of 147 patients who underwent early LT (without 6 mo of abstinence) for SAH reported a 1-year survival rate of 94% and 3-year survival rate of 84%, and sustained alcohol use after LT was infrequent but associated with increased mortality, as reported by the American Consortium of Early Liver Transplantation for AH[83]. A retrospective analysis of 17 Chinese ALD patients who received LT found that survival rates at 25, 50, and 100 wk after LT were 94.1% (16/17), 82.4% (14/17), and 64.7% (11/17), respectively[84]. Another follow-up study of 40 LT patients from April 2005 to June 2017 showed that the 1-year survival rate was 81.0% and the 5-year survival rate was 77.0%, and these rates were comparable to outcomes reported in other countries[85]. However, the mortality of SAH remains high, because the shortage of donor organs and high cost of surgery limit patients’ access to LT[86].

Alcohol consumption is impacted by alcohol and taxation policies as well as social and cultural norms. In China, the alcohol taxes were increased in 2002, and the alcohol sale restrictions and the license requirement were implemented in 2004. In 2007, the laws that punish drunk drivers began to be enforced, and restrictions on alcohol advertisements took effect in 2010[87]. However, the alcohol policy in China is weaker than those in its neighboring countries in many aspects, which favors alcohol consumption, leading to consequent alcohol-related problems. There are no minimal legal age requirements for purchasing or selling alcoholic beverages, no restrictions on home-made alcohol beverages, no enforceable regulations on alcohol sponsorship/sale promotion, and no legal requirements for warning labels on alcohol advertisements/containers in China[7,87]. We advocate a strong and sensible alcohol policy that effectively regulates alcohol production quality and consumption to reduce the occurrence of ALD in China[88].