BINGE DRINKING AS A RISK FACTOR FOR ADVANCED ALCOHOLIC LIVER DISEASE

Globally, alcoholic liver disease (ALD) is a leading cause of liver-related morbidity and mortality (1). According to the World Health Organization (WHO), alcohol use is attributed to approximately half of all cirrhosis cases worldwide. Despite the medical and economic burden, the incidence, natural history, and modifying factors of ALD remain largely unknown. Alcoholic liver disease encompasses a range of disorders including simple steatosis, steatohepatitis, fibrosis, cirrhosis (with or without superimposed alcoholic hepatitis), and hepatocellular carcinoma (HCC). Patients with decompensated disease and/or HCC are faced with poor prognosis and a high mortality rate. Identification of risk factors which predispose heavy drinkers to develop advanced forms of ALD is mandatory in order to implement health policies to prevent this deadly condition.

Apart from genetic factors, evidence indicates the amount of alcohol intake heavily influences the development of advanced ALD. There exists a direct relationship between the amount of alcohol consumed (>30 g/day in most studies) and the probability of developing ALD (2). In a large European study enrolling patients with different stages of ALD, an intake of 400 g ethanol/week strongly increased the risk of developing cirrhosis (30%) during follow-up (3). In addition to the amount of alcohol intake, it has been proposed that the pattern of alcohol drinking also plays a role in disease progression. For example, red wine drinkers have a lower risk of cirrhosis than consumers of other alcoholic beverages (4, 5). Moreover, patients who drink alcohol outside of meals may have an increased risk of cirrhosis (6). Currently, much research attention is afforded to binge drinking; a pattern based on heavy episodic alcohol intake in a brief period of time. There are several definitions of binge drinking. According to the National Institute in Alcohol and Alcoholism (NIAAA), it is a pattern of drinking which increases the blood alcohol concentration levels to at least 0.08 g/dL. This typically occurs after 4 drinks for women and 5 drinks for men in about two hours (7). According to the WHO, binge drinking consists of 5 and more standard drinks per day on at least one occasion during the last 30 days. Furthermore, according to the Alcohol Use Disorders Identification Test (AUDIT), it consists of 6 or more drinks on one occasion. There is no doubt binge drinking is associated with increased violence and accidents (8), yet its role as a risk factor for cirrhosis is unclear. While it is generally accepted binge drinking exacerbates ALD, the human data supporting this notion is scarce (Table 1). In fact, some data suggest that “binge” drinking is less likely to lead to cirrhosis or alcoholic hepatitis compared to continuous drinking (9–11) (Table 1). As the underlying mechanisms of binge drinking remain elusive, further research is needed to clarify the role it plays in increasing the risk of advanced ALD.

Table 1.

Human studies assessing the effects of binge drinking

Reference	Study population and type of intervention	Main effect	Type of study	Patter of alcohol intake*
Bala 2014 (13)	a) Healthy individuals n= 24 b) Control subjects n=4 2 ml vodka 40% v/v ethanol/kg body weight in a total volume of 300 ml of juice	• Serum endotoxin ↑ • Serum 16S rDNA ↑ • LBP and CD14 ↑	Intervention study	Binge (NIAAA definition)
Oekonomaki et al, 2004 (14)	a) Viral hepatitis n=13 b) Viral cirrhosis n=9 c) Alcoholic cirrhosis n=15 d) Healthy n=7 80g OH group a and b vs. no intervention in groups c and d	• NOx ↑ in groups a and b vs. d c vs. d	Intervention study	Binge (NIAAA definition)
Yun et al, 2014 (15)	Autopsy human specimens a) Binge drinkers (n=12) b) No drinkers (n=12)	• Hepatic HIF-1α, p53, BNIP3, Bax and iNOS and CYP2E1 activity ↑ • Correlations between BAC and CYP2E1, HIF-1α, iNOS	Cohort study	Binge (NIAAA definition)
Ruhl et al, 2005 (16)	13,580 adult participants in the third United States National Health and Nutrition Examination Survey, 1988–1994	• Binge drinking was associated with aminotransferase elevation in obese having 1–2 drinks per day.	Cohort study	Binge (WHO definition)
Lau et al, 2015 (17)	4,009 adults from a North-east Germany cohort	• Binge drinking was associated with hepatic steatosis in men • Binge drinking in combination with overweight or obesity favor hepatic steatosis.	Cohort study	Binge (WHO definition)
Stokkeland et al, 2008 (9)	a) Patients with alcoholic cirrhosis (n=50) b) Alcoholic dependence without liver disease (n=50) c) No alcoholic cirrhosis (n=40)	• Binge drinking, rather than continuous drinking, was not associated with cirrhosis	Cohort study	Binge (WHO definition)
Åberg et al, 2017 (21)	6,366 subjects without baseline liver from a Finnish population-based Health 2000 Study (2000–2001)	Increase risk of DLD in: Weekly/monthly binge Weekly binge showed additive risk with metabolic syndrome	Cohort study	Binge (WHO definition)
Liangpunsakul et al, 2016 (11)	a) AH patients n=145 b) Control subjects n=124	AH patients had less binge drinking compare to control subjects	Cohort study	Binge (NIAAA and AUDIT definitions)

^*Definitions of BINGE DRINKING: NIAAA: a pattern of drinking that brings blood alcohol concentration levels to 0.08 g/dL. This typically occurs after 4 drinks for women and 5 drinks for men in about 2 hours. WHO: 5 and more standard drinks per day on at least one occasion during the last 30 days. AUDIT: 6 or more drinks on one occasion.

Alcoholic hepatitis, AH; Lipopolysaccharides, LBP; Nitrites and nitrates, NOx, Alcohol, OH; BCL2 Associated X, Apoptosis Regulator, BAX; Hypoxia Inducible Factor 1 Alpha Subunit, HIF-1α; BCL2 Interacting Protein 3, BNIP3; Cytochrome P450 2E1, CYP2E1; Blood alcohol concentration, BAC; Inducible nitric oxide synthase, iNOS; Alcohol Dehydrogenase; ADH; decompensated liver disease, DLD; National Institute of Alcohol Abuse and Alcoholism, NIAAA; World Health organization, WHO; Alcohol Use Disorders Identification Test, AUDIT.

Increasing evidence supports the notion that acute alcohol intake has deleterious effects in humans and rodents. In humans, binge drinking has been shown to increase serum lipopolysaccharide (LPS) levels, a key mediator of ALD (12, 13) as well as nitric oxide metabolites (14). Other studies suggest a correlation between the binge pattern and activation of CYP2E1-HIF-1α-dependent apoptosis pathway (15). Interestingly, two epidemiological studies showed a higher impact of binge alcohol drinking pattern on obese or overweight patients (16, 17). The most convincing evidence supporting the role of binge drinking on ALD progression derives from experimental studies (18, 19). In a recently developed mouse model, chronic-plus-binge ethanol feeding synergistically induced steatosis, liver injury, and hepatic neutrophil infiltration in mice. Using this chronic-plus-binge alcohol model, researchers have begun to identify novel mechanisms that participate in the pathogenesis ALD, thereby revealing novel therapeutic targets (20).

In this issue of Liver International, Åberg et al. (21) used a Finnish population-based health study to address this question. Out of 6,000 individuals, 84 patients developed advanced liver disease. Interestingly, binge-drinking frequency showed a near-linear association with liver-disease risk after adjustment for average daily alcohol intake and age. The hazard ratio (HR) for weekly binge drinking was 6.82 in subjects with metabolic syndrome. Weekly binge drinking, in combination with metabolic syndrome, produced a superadditive increase in the risk of decompensated liver disease. The authors of this study deduce binge drinking is associated with an increased risk for liver disease, independent of average alcohol intake. This effect is pronounced in patients with metabolic syndrome.

Results from this study (Åberg et al.) establish important clinical implications. First, it provides evidence binge drinking can lead to more severe forms of ALD, in some cases requiring hospitalization. Thus, public health measures aimed at reducing the alarming prevalence of binge drinking in the youth population should be implemented. Second, by showing that different patterns of alcohol intake may impact the severity of organ damage, it reinforces the need to collect detailed information on drinking patterns in future prospective studies. Finally, it demonstrates that alcohol abuse and metabolic syndrome can synergistically increase development of severe ALD. Such synergistic effects have been suggested by several human and experimental studies. In fact, daily intake of 3 or more drinks in patients with obesity predisposes to liver injury and the development of cirrhosis. Similarly, the presence of obesity in very heavy drinkers markedly increases the rate of cirrhosis and liver-related decompensation (6, 22, 23). At the experimental level, high fat diet and alcohol intake are clearly synergistic in inducing liver injury (20). Although some epidemiological studies suggest daily intake of one cup of wine could protect from the development of fatty liver (24), there is mounting evidence indicating that alcoholic and metabolic syndrome synergistically induce advanced liver disease (i.e. cirrhosis). The study by Åberg et al. supports this assumption. Providers should pay more attention to identify hazardous alcohol patterns in patients with metabolic syndrome and provide support to reduce alcohol intake. Conversely, heavy drinkers should be cautioned to the risks combined with obesity. This common clinical problem is often overlooked in clinical hepatology and deserves more attention from public health, clinical, and research perspectives.

In conclusion, the epidemiological study by Åberg et. al points to binge drinking, independent of daily alcohol intake, as a risk factor for advanced liver disease. This study seeks to raise awareness of the deleterious repercussions episodic heavy drinking renders in organ damage. To reduce the burden of binge drinking, public health campaigns should target younger populations most susceptible to the harmful patterns of this common way to consume alcohol.

Abbreviations

ALD

Alcoholic liver disease

WHO

World Health Organization

HCC

hepatocellular carcinoma

NIAAA

National Institute in Alcohol and Alcoholism

AUDIT

Alcohol Use Disorders Identification Test

LPS

Lipopolysaccharide

CYP2E1

Cytochrome P450 2E1

HIF-1-α

Hypoxia Inducible Factor 1 Alpha Subunit