sign in sign up
<<
Home , Binge drinking

RESEARCH: Current Reviews

Binge Drinking’s Effects on the Body

Patricia E. Molina and Steve Nelson Patricia E. Molina, M.D., Ph.D., is the Richard Ashman, Studies have focused on the effects of chronic alcohol consumption and the mecha- Ph.D., Professor; head of the nisms of tissue injury underlying and , with less focus on Department of Physiology; and the pathophysiological consequences of binge alcohol consumption. Alcohol binge drinking prevalence continues to rise, particularly among individuals ages 18 to 24. director of the Comprehensive However, it is also frequent in individuals ages 65 and older. High blood alcohol levels Alcohol–HIV/AIDS Research achieved with this pattern of alcohol consumption are of particular concern, as alco- Center and the Alcohol and hol can permeate to virtually all tissues in the body, resulting in significant alterations Center of Excellence, in organ function, which leads to multisystemic pathophysiological consequences. In Louisiana State University Health addition to the pattern, amount, and frequency of alcohol consumption, additional Sciences Center, New Orleans, factors, including the type of alcoholic beverage, may contribute differentially to the Louisiana. risk for alcohol-induced tissue injury. Preclinical and translational research strategies are needed to enhance our understanding of the effects of binge alcohol drinking, Steve Nelson, M.D., is the particularly for individuals with a history of chronic alcohol consumption. Identifica- John H. Seabury Professor of tion of underlying pathophysiological processes responsible for tissue and organ Medicine and the dean of the injury can lead to development of preventive or therapeutic interventions to reduce School of Medicine, Louisiana the health care burden associated with binge alcohol drinking. State University Health Sciences Key words: Alcohol and other drug (AOD) intoxication; alcoholic hepatitis; Center, New Orleans, Louisiana. alcoholic liver cirrhosis; alcohol-induced disorders; binge drinking;

Introduction the individual, has been well-estab- equivalents in tissue has been consis- lished.3,4 The resulting tissue injury tently demonstrated to be an overall Alcohol misuse is the fifth-leading has increasingly been recognized and mechanism of the tissue injury that risk factor for premature death and dis- examined as a contributing factor to results from chronic alcohol misuse. ability worldwide,1 and, adjusting for alcohol-related comorbidities and Dose-dependent relationships between age, alcohol is the leading risk factor mortality. Several pathophysiological alcohol consumption and incidence for mortality and the overall burden mechanisms have been identified of diabetes mellitus, hypertension, of disease in the 15 to 59 age group.2 as causative factors of tissue and ischemic disease, dysrhythmias, According to the World Health organ injuries that resulted from , pneumonia, and fetal alco- Organization, in 2004, 4.5% of the excessive alcohol consumption, hol syndrome have been reported.4 global burden of disease and injury was including acetaldehyde generation, However, recognition of alcohol as an attributable to alcohol: 7.4% for men adduct formation, mitochondrial underlying causal factor in comorbid and 1.4% for women.2 injury, cell membrane perturba- conditions remains a challenge in the Alcohol can permeate to virtually tions, immune modulation, and clinical setting. all tissues in the body, resulting in oxidative stress (Figure 1). Some Several factors associated with significant alterations in organ func- of these mechanisms are the result alcohol consumption, including pat- tion, which leads to multisystemic of direct alcohol-induced cell per- tern, amount, and frequency, and pathophysiological consequences. turbations, whereas others are the the type of alcoholic beverage, may The effect of alcohol misuse on mul- consequence of tissue alcohol me- contribute differentially to the risk tiple organ systems outside the liver, tabolism (Figure 2). The oxidative for alcohol-induced tissue injury. The mediated through direct and indirect stress caused by excess production question of whether all types of alcohol effects beyond those associated with of reactive oxygen species (ROS) or produce similar pathophysiological alterations in the nutritional state of a reduction in reducing antioxidant consequences remains to be answered.

Binge Drinking’s Effects on the Body | e1 However, the particularly detrimental effects of binge drinking have increas- ingly gained attention. Binge drinking, as defined by the National Institute on and (NIAAA), is a pattern of alcohol con- sumption that brings blood alcohol concentration to .08 g/dL, which typically occurs following the intake of five or more standard alcohol drinks by men and four or more by women over a period of approximately 2 hours.5 Results from the 2015 National Survey on Drug Use and Health show overall prevalence of binge drinking (during the past 30 days) of 26.9% among U.S. adults ages 18 and older.6 Those data show that binge drinking preva- lence and intensity are highest among those ages 18 to 24 but also occur in high frequency among older individ- uals (ages 65 and older). Thus, binge drinking prevails in two vulnerable segments of the population, raising their risks for greater severity of injury and frequency of comorbidities.

Understanding the Biomedical Consequences of Binge Drinking A limitation to our understanding of the consequences of binge alcohol con- sumption on organ injury is the lack of information on the time period, duration, and number of binge oc- currences that describe the long-term practice of binge drinking. Preclinical studies conducted under controlled conditions provide opportunities to examine quantity and frequency vari- ables in the investigation of the effects of alcohol consumption on organ Figure 1 Mechanisms of alcohol-induced tissue injury. Alcohol contributes to tissue injury injuries. However, interpreting, com- directly and indirectly through mechanisms including oxidative stress, inflammation, paring, and integrating the patterns of acetaldehyde adduct formation, barrier integrity disruption, decreased anabolic alcohol consumption described in clin- signaling, enhanced catabolic processes (particularly through the ubiquitin ical reports is difficult because of the proteasome pathway), profibrotic changes, mitochondrial dysfunction and injury, different types of data collected across and cell membrane perturbations. Note: mTORC1, mammalian target of rapamycin studies. This difficulty underscores the complex 1; mTORC2, mammalian target of rapamycin complex 2; ROS, reactive need for researchers to perform more oxygen species. Source: Molina PE, Gardner JD, Souza-Smith FM, et al. Alcohol rigorous comprehensive and systematic abuse: Critical pathophysiological processes and contribution to disease burden. data collection on alcohol use patterns. Physiology. 2014;29(3)203-215. The Timeline Followback (TLFB) tool, for example, uses a calendar and e2 | Vol. 39, No. 1 Alcohol Research: Current Reviews Figure 2 Tissue alcohol metabolism contributes to tissue and organ injury through altered redox potential, generation of ROS, and generation of metabolites, such as acetaldehyde, that form DNA and protein adducts. Alcohol () is metabolized to acetaldehyde primarily by ADH in the cytosol and CYP2E1 in the endoplasmic reticulum. Acetaldehyde is converted to acetate in the mitochondria by the enzyme ALDH. Acetaldehyde can form adducts with DNA and proteins that can produce injury through activation of immune responses. During the oxidative process, both ADH and ALDH reactions reduce NAD+ to NADH, shifting the cellular redox ratio. In addition, the cytochrome P450 enzymes, particularly CYP2E1, contribute to the oxidation of alcohol to acetaldehyde, particularly at increasing alcohol concentrations, as well as following their induction by chronic alcohol misuse. The pathway of alcohol oxidation results in the production of large amounts of ROS,

including H2O2, and is thought to be an important mechanism contributing to alcoholic liver injury. ROS are eliminated by antioxidants like GSH under normal conditions. Alcohol depletes cellular GSH stores, thereby exacerbating ROS-mediated injury. ROS can interact with lipids, producing lipid peroxidation, which leads to formation of reactive molecules such as MDA and HNE, which can then form protein adducts. Note: Acetyl-CoA, acetyl coenzyme A; ADH, alcohol dehydrogenase; ALDH, acetaldehyde dehydrogenase type 2; CYP2E1, cytochrome

P450 2E1; GSH, glutathione; H2O, water; H2O2, hydrogen peroxide; HNE, 4-hydroxy-2-nonenal; MDA, malondialdehyde; NAD+, nicotinamide adenine dinucleotide (oxidized); NADH, nicotinamide adenine dinucleotide (reduced); NADP, nicotinamide adenine dinucleotide phosphate

(oxidized); NADPH, nicotinamide adenine dinucleotide phosphate (reduced); O2, oxygen; ROS, reactive oxygen species. Source: Molina PE, Gardner JD, Souza-Smith FM, et al. Alcohol abuse: Critical pathophysiological processes and contribution to disease burden. Physiology. 2014;29(3)203-215.

a structured interview to collect ret- should be taken into consideration the health consequences associated rospective information on the types for future development of alcohol use with binge drinking. Epidemiological and frequency of alcohol use over a screening tools, because binge drinking studies that compared the preva- given time period.7,8 Nevertheless, has been suggested to result in greater lence of coronary heart disease in accounting for a lifetime pattern of alcohol-related harm.9 “-drinking countries” and - or binge alcohol consumption remains Different types of alcoholic bev- -drinking countries have pro- challenging when conducting clinical erages consumed in binge drinking posed that red wine, but not beer or studies. Alcohol consumption patterns episodes could also differentially affect spirits, consumed with a meal may

Binge Drinking’s Effects on the Body | e3 confer cardiovascular protection.10 binge drinking is more likely to con- cidated. However, it is reasonable to The proposed protective effects of red tribute to organ injury than paced, speculate that greater bacterial burden wine include decreased blood clot moderate alcohol drinking that is asso- and altered bacterial profiles, together formation, vascular relaxation, and ciated with a meal. with increased permeability of the gut attenuation of low-density lipoprotein The gut mucosa is particularly sus- mucosa, would lead to continuous en- (LDL, or bad cholesterol) oxidation, ceptible to alcohol-induced injury, try of bacterial toxins into the systemic an early event preceding formation of and alcohol consumption can result circulation. These changes could pro- cholesterol-filled plaque. These effects in a loss of intestinal barrier integrity. duce chronic and sustained activation are attributed to polyphenols, espe- Several direct and indirect mechanisms of immune responses that, in turn, cially resveratrol, and their antioxidant have been identified that disrupt the could lead to immune exhaustion and properties. structural and functional components dysfunction. Preclinical studies show However, not all reports support the involved in maintaining the integrity that binge-on-chronic alcohol feeding link between consuming a specific bev- of the gut mucosal barrier. Alcohol alters the gut microflora at multiple erage type (i.e., wine vs. beer or spirits) and its breakdown products directly taxonomic levels, influencing hepatic and health benefits. Some reports damage epithelial cells through gener- inflammation, neutrophil infiltration, suggest that beverage amount is more ation of ROS and through disruption and liver steatosis,23 which highlights directly linked to health outcomes.11,12 of tight junction protein expression the need for clinical investigation into The differential contribution of alco- and signaling.14 This process disrupts the relationship between gut micro- holic beverages to beneficial or detri- the integrity of the intestinal barrier, flora and hepatic liver disease. mental health outcomes remains to be allowing bacteria and toxins to reach examined in both preclinical and clini- the bloodstream. Acute alcohol binge cal studies. In binge drinking episodes, drinking in healthy human volunteers Local and Systemic the form of alcohol consumed most can produce a significant increase in Consequences of Gut Injury frequently is beer (67.1%), followed serum endotoxin levels and bacterial by liquor (21.9%) and wine (10.9%).13 16S ribosomal DNA, suggesting the Toxins and bacterial products leaked Moreover, beer accounts for most of gastrointestinal microbial origin of from the can be the alcohol consumed by drinkers endotoxin.15-17 transported through the lymphatic who are at the highest risk of causing More recently, attention has system. This route of dissemination, or incurring alcohol-related harm, focused on the changes in intestinal which escapes hepatic clearance, may including drinkers ages 18 to 20, those microbiome that contribute to alcohol- prove critical in the enhanced systemic with more frequent binge episodes per associated intestinal inflammation delivery of toxins. Preclinical studies month, and those drinking 8 or more and permeability. Alcohol promotes have shown that repeated binge-like drinks per binge episode. Therefore, both dysbiosis (decreased diversity increases lym- dissecting how pattern of drinking and or an imbalance in the types of phatic permeability and inflammation type of alcoholic beverage contribute microbes) and bacterial overgrowth in the adipose tissue that immediately to overall outcomes is challenging. in the gastrointestinal system.18-21 surrounds the mesenteric lymphatics. Alcohol alters the balance between Inflammatory response in mesenteric bacterial strains, decreasing the perilymphatic adipose tissue is associ- The Gastrointestinal Tract, presence of beneficial bacteria, such as ated with altered adipose tissue insulin Liver, and Pancreas Lactobacillus and Bifidobacterium, and signaling and circulating adipokine increasing that of Proteobacteria and profiles, which suggests a link between Of all tissues affected by binge-like Bacilli.19 This imbalance adds to the lymphatic leak, adipose tissue inflam- alcohol consumption, the gastrointes- possibility that bacterial overgrowth mation, and metabolic dysregulation.24 tinal tract bears the greatest burden may contribute to local mucosal Whether chronic alcohol consump- due to its direct exposure to high tissue inflammation through bacterial tion not in a binge pattern produces concentrations of alcohol following metabolism of alcohol and enhanced similar alterations in lymphatic per- ingestion (Figure 3). Binge drinking local production of metabolites such meability and mesenteric adipose often occurs apart from meals, which as acetaldehyde.22 Moreover, increased inflammation remains to be deter- may also contribute to its deleterious bacterial load, together with shifts in mined. However, localized alterations effects on organs. Food consumed at intestinal bacterial strains, brings about in mesenteric adipose tissue metabolic the time of alcohol consumption influ- diverse profiles of bacterial-derived regulation, including insulin signal- ences not only the alcohol absorption metabolites. ing, may prove to be relevant to the rate and blood alcohol concentration, How these shifts in bacterial strains, enhanced risk for metabolic syndrome but also the direct effect of alcohol on load, and metabolites contribute to that is associated with binge alcohol the gastrointestinal mucosa. Hence, organ injury remains to be fully elu- consumption.25 After burn injury e4 | Vol. 39, No. 1 Alcohol Research: Current Reviews Gastrointestinal Cardiovascular Pulmonary system Musculoskeletal Nervous system tract, liver, and system • Oxidative stress system • Impaired behavioral pancreas • Cardiomyocyte and diminished • Decreased growth and cognitive • Esophageal and mitochondrial lung host defense factor signaling function, impaired gastric dysmotility and sarcoplasmic mechanisms and responsiveness, impulse control and • Liver oxidative stress, reticulum damage, increased ubiquitin motor skills, and steatosis, hepatitis, altered calcium proteasome blackouts and fibrosis dynamics, and pathway activation, • Structural changes in • and cardiac fibrosis upregulation of prefrontal and parietal mucosal atrophy • Myocardial negative regulators regions, and - • Impaired intestinal oxidative of skeletal muscle specific differences nutrient absorption, stress, impaired growth, and in frontal, temporal, disruption of cardiomyocyte disruption of bone and cerebellar brain intestinal barrier and contraction, remodeling activation during lymphatic function, hypertension, and working memory tasks and increased potentiation of the • Enlargement of lateral bacterial toxin renin-angiotensin- ventricles and cisterns, translocation aldosterone system and degradations in • Increased pancreas neural white matter inflammation • Reduced • Increased neuroimmune gene expression

Figure 3 The systemic effects of chronic binge alcohol consumption and the principal organ systems affected.

and a binge-like pattern of alcohol metabolism of alcohol and the result- aminotransferase), hepatic steatosis, intoxication, rodents showed similar ing ROS generation; acetaldehyde and inflammatory cytokine expression exacerbation of adipose tissue inflam- formation and the resulting adducts; compared to rodents subjected only to mation.26 This suggests that a possible immune response activation, partic- chronic or to acute alcohol exposure.32 synergism between binge-like alcohol ularly in Kupffer and stellate cells; These results demonstrate that binge- intoxication and injury promotes a and alterations in cell signaling are all on-chronic alcohol exposure results in dysregulated adipose environment proposed as mechanisms that underlie greater insult than either chronic or conducive to insulin resistance, and liver injury associated with binge-like acute alcohol exposure alone. Clinical potentially metabolic syndrome, if alcohol consumption. For people with studies have provided evidence of these alterations are sustained beyond chronic alcoholism, binge drinking associations among alcohol binge the immediate period following binge augments liver injury27,28 and is a ma- drinking patterns, immune activation drinking or burn injury.3 jor trigger for the progression from (high CD69 and low TLR4, CXCR4, Second to the gastrointestinal tract, steatosis to steatohepatitis.29-31 In one and CCR2 expression), and decreased the liver has the most exposure to high study, rodents that received binge-on- chemotactic responses to SDF-1 and alcohol concentrations during periods chronic alcohol exposure had accentu- MCP-1.33 These associations reflect an of binge drinking. Hepatocellular ated elevation in liver enzymes (alanine altered immune profile that may be as-

Binge Drinking’s Effects on the Body | e5 sociated with liver injury and increased levels of alpha-amylase, glucose, and Binge drinking has been associated susceptibility to infection. More re- insulin, strongly suggesting a detri- with increased risk of cardiovascular cently, attention has been drawn to mental effect of acute binge alcohol comorbidities, including hypertension, the potential greater liver injury in exposure on the pancreas. Specifically, stroke, , and individuals with metabolic syndrome. preclinical studies have proposed that, sudden death, and this risk may extend A population-based study showed a alone, chronic and binge alcohol expo- to the younger population as well.47-51 direct association between binge drink- sure caused minimal pancreatic injury, Acute elevations in blood alcohol levels ing frequency and liver disease risk, but chronic plus binge alcohol expo- resulting from binge alcohol consump- after adjusting for average daily alcohol sure resulted in significant apoptotic tion are associated with an increased intake and age.34 In this study, binge cell death; alterations in alpha-amylase, risk of new-onset , a drinking and metabolic syndrome glucose, and insulin; pancreatic in- most common arrhythmia strongly produced supra-additive increases flammation; and protein oxidation and associated with adverse cardiovascular in the risk of decompensated liver lipid peroxidation, which are indicative events and sudden death.52 A higher disease. Because of increasing rates of of oxidative stress.37 The pathogene- risk for myocardial infarction has obesity and metabolic syndrome, re- sis of alcoholic involves been reported after 1 day of heavy search on the effects of alcohol misuse acinar cell alcohol metabolism. The alcohol consumption (which could and the biomedical consequences is direct toxic effects of alcohol and its reflect a binge-like pattern of alcohol needed for this particular segment of metabolites on acinar cells, in the pres- consumption).53 the population. ence of an appropriate trigger factor, Few preclinical studies have exam- Located strategically between the may predispose the gland to injury. ined the effect of binge drinking on liver and the gastrointestinal tract, In addition, pancreatic stellate cells cardiac function. In one study, over the pancreas also has high susceptibil- are implicated in alcoholic pancreatic a 5-week period, rodents received ity to alcohol-induced tissue injury. fibrosis.38 Thus, experimental and repeated episodes of alcohol adminis- Heavy, chronic alcohol consumption clinical data suggest that alcohol con- tration that modeled a binge drinking is a recognized contributing factor sumption alone does not initiate pan- pattern.54 These rodents did not show in the development of pancreatitis. creatitis, but it sensitizes the pancreas changes in cardiac structure, but this However, how dose and pattern of to disease from other insults, including drinking pattern resulted in increased alcohol consumption affect pancreatic smoking, exposure to bacterial toxins, phosphorylation of myocardial p38 function and structure is not known. viral infections, and binge alcohol mitogen-activated protein kinase and Studies show that alcohol consump- consumption.39 transient increases in , tion of more than 40 g per day is which became progressively higher increasingly detrimental for any type with repeated episodes of binge of pancreatitis.35 Retrospective clinical Cardiovascular Consequences drinking. These effects were partly studies have shown that binge alcohol mediated by adrenergic mechanisms. drinking is associated with aggravation The effect of alcohol consumption More recently, the combined binge- of first-attack severe acute pancreatitis, on cardiovascular function has been on-chronic pattern of alcohol feeding which is reflected in higher admission the subject of much debate. The rela- to rodents has been shown to result levels of serum triglycerides, Balthazar tionship between alcohol consumption in alcohol-induced cardiomyopathy, computed tomographic score, and and cardiovascular health is not linear characterized by increased myocardial Acute Physiology and Chronic and is thought to follow a J-shaped oxidative/nitrative stress, impaired mi- Health Evaluation II score, as well curve, with low amounts of alcohol tochondrial function and biogenesis, as higher mortality and incidence of consumption frequently reported as and enhanced cardiac steatosis.55,56 The 40 complications.36 cardioprotective. However, data sug- role of oxidative stress has been con- Insight into the mechanisms in- gest that binge drinking is associated firmed by other preclinical studies.57 volved in pancreatic injury is derived with transient increases in systolic and from preclinical studies that show diastolic blood pressure (Figure 3).41-43 detrimental effects of binge alcohol The prevalence of hypertension has Pulmonary Consequences exposure on the pancreas. These effects been reported to be higher in indi- include tissue edema, inflammation, viduals who consume more than six Preclinical studies have identified acinar atrophy and moderate fibrosis, drinks per day. However, the pattern impairments in multiple aspects of endoplasmic reticulum stress, oxidative of alcohol consumption was not con- lung function after chronic and binge- stress, and apoptotic and necrotic cell sidered in these studies.44 The effect of like alcohol administration, including death. These structural changes are as- even a modest rise in blood pressure is altered epithelial barrier function, sup- sociated with pancreatic dysfunctional considerable, as it is a recognized risk pressed immunity, impaired bacterial changes, which are reflected by altered factor for cardiovascular mortality.45,46 clearance, depleted glutathione (GSH), e6 | Vol. 39, No. 1 Alcohol Research: Current Reviews and impaired pulmonary epithelial cil- Preclinical studies suggest that, after trol, impairments in motor skills (e.g., iary function (Figure 3).58,59 Moreover, binge-like alcohol administration, balance and hand-eye coordination), alcohol binge drinking increases the physical exercise may ameliorate cog- blackouts, and loss of consciousness risk for sustaining traumatic injuries nitive impairment and suppressed neu- (Figure 3).80 All of these effects have and aggravates outcomes from trau- rogenesis.73 The effect of binge alcohol serious health consequences ranging matic injuries,60 such as burns,26,58,61-63 consumption on exercise performance from falls and injuries to death.81 In bone fractures,64 and hemorrhagic and recovery remains to be systemat- particular, adolescents are vulnerable shock.65 For alcohol-intoxicated hosts, ically investigated. One clinical study to the cognitive manifestations and similar detrimental effects have been reported no change in isokinetic and memory loss associated with binge reported on bacterial pneumonia out- isometric muscle performance, central drinking. National estimates suggest comes, a frequent comorbid condition activation, or creatine kinase release that significant numbers of people associated with traumatic injury.66 during or after acute moderate alcohol who binge drink report at least one Binge-like alcohol administration intoxication.74 Short-term reductions incident of blacking out in the pre- impairs innate and adaptive immune in lower-extremity performance were vious year.82,83 Blackouts, defined as responses in the lungs, thereby increas- reported in a study that investigated short periods of amnesia during which ing infection susceptibility, morbidity, athletes after an alcohol drinking a person actively engages in behaviors and mortality.61,62 It is possible that, episode and the associated reduced (e.g., walking or talking) without in hosts previously exposed to chronic sleep hours.75 Another study found creating memories for them, often alcohol consumption, binge drink- that alcohol consumption following occur at blood alcohol concentrations ing detrimentally affects pulmonary a simulated rugby game decreased exceeding .25 g/dL.84,85 Blackouts are outcomes from traumatic injury by lower-body power output but did not common among college students who priming host defense mechanisms. affect performance of tasks requiring drink alcohol. Estimates suggest that This combined effect may prevent clear repeated maximal muscular effort.76 up to 50% of students that engaged in isolation of binge alcohol consumption However, the same researchers found drinking reported a blackout episode effects from chronic alcohol consump- that alcohol consumption following during the past year.86,87 The pattern tion effects. eccentric exercise accentuated the of rapid consumption of large doses losses in dynamic and static strength of alcohol, frequently on an empty in males.77 stomach, is characteristic of the adoles- Musculoskeletal Consequences In contrast, alcohol consumption cent period.88 following muscle-damaging resistance The consequences of binge drinking The incidence of skeletal muscle exercise did not alter inflammatory are not short-lived or limited to the pe- dysfunction (i.e., myopathy) resulting capacity or muscular performance re- riod of intoxication. Imaging studies of from chronic alcohol misuse surpasses covery in resistance-trained women,78 binge drinking adolescents document that of cirrhosis.67 This progressive suggesting possible gender differences long-lasting changes. Reports indicate loss of mass is multifactorial and in alcohol’s modulation of exercise per- structural changes in the prefrontal involves metabolic, inflammatory, and formance and recovery. These studies and parietal regions, as well as in re- extracellular matrix alterations, which were conducted using healthy volun- gions known to mediate reward, and promote muscle proteolysis and de- teers and athletes. Other studies that these changes are thought to reflect creased protein synthesis (Figure 3).68 investigated patients with alcoholic long-lasting effects of alcohol bingeing An additional severe complication of liver disease showed lower muscular on critical neurodevelopmental pro- binge drinking is the development of endurance, maximal voluntary isomet- cesses.89 Functional imaging studies acute muscle injury, rhabdomyolysis. ric muscle strength, and total work of of the brains of binge drinking and Binge drinking that precedes coma or knee extensors.79 Controlled studies nondrinking adolescents found that immobility can lead to rhabdomyolysis are needed, particularly in light of the binge drinking adolescents showed and, consequently, to renal injury, popularity of binge drinking events greater responses in frontal and parietal as documented in case reports in the frequently associated with collegiate regions, no hippocampal activation to literature.69-71 The mechanisms are not and professional sports. novel word pairs, and modest decreases well-understood, but they may involve in word-pair recall, which could in- acute hypokalemia.72 This phenom- dicate disadvantaged processing of enon may warrant further study, as Neuropathological novel verbal information and a slower environmental factors such as high Consequences learning slope.90 In another study, ambient temperature and individual adolescent binge drinking resulted in drug-drug interactions can obscure The behavioral and cognitive effects gender-specific differences in frontal, presentation and hinder management of binge drinking include difficulties temporal, and cerebellar brain activa- of alcohol-induced rhabdomyolysis. in decision-making and impulse con- tion during a special working memory

Binge Drinking’s Effects on the Body | e7 task, reflecting differential effects of administration to rodents produced hepatitis and cirrhosis have received binge drinking on neuropsychologi- increases in cerebrospinal fluid volume much attention, less attention has been cal performance and possibly greater in the lateral ventricles and cisterns, focused on the pathophysiological vulnerability in female adolescents.91 decreased levels of N-acetylaspartate consequences of binge alcohol con- Other researchers have reported that and total creatine, and increased sumption. The differential duration degradations in neural white matter choline-containing compounds, of the intoxication period, excessive were linked with impaired cogni- glutamate, and glutamine, all of concentrations of alcohol at the tissue tive functioning in adolescents who which recovered during abstinence.94 92 level, accelerated alcohol metabolism binge drank. Moreover, preclinical data suggested and generation of ROS and alcohol Adolescent rodent intermittent eth- that adolescent binge drinking sensi- metabolites, and acute disruption of anol exposure that modeled human tized the neurocircuitry of , adolescent binge drinking produced a antioxidant mechanisms are some of possibly inducing abnormal plasticity the salient differences between chronic range of pathophysiological and neuro- in reward-related learning processes, and binge-like alcohol-mediated tissue behavioral sequelae, including altered which could contribute to adolescent adult synapses, cognition, and sleep; vulnerability to addiction.95 injury. Because of the differences in reduced adult neurogenesis; increased male and female alcohol metabolism neuroimmune gene expression; and rates, it is possible that greater tissue increased adult alcohol drinking associ- Summary injury is produced in females who con- ated with disinhibition and social anx- sume alcohol in binge-like patterns. iety.93 Preclinical studies indicated that Although the effects of chronic alco- Furthermore, in an aging population binge drinking could produce brain hol consumption and the mechanisms already riddled with polypharmacy, structural abnormalities. Binge alcohol of tissue injury underlying alcoholic there is heightened potential for toxic- ity during an alcohol binge (Figure 4). Also, pre-existing comorbid conditions such as cardiovascular disease, renal failure, or steatohepatitis may pre- dispose binge drinkers to accelerated tissue injury. Additional research is needed to bet-

in ter recognize the differential effects of binge, chronic, and binge-on-chronic patterns of alcohol consumption. Animal models that reflect these pat- nvironment iat iet terns of alcohol exposure are needed. In addition, greater effort toward documenting a history of alcohol con-

ine lcool sumption, including the frequency, quantity, and quality of alcoholic beverages consumed, should help us Polyparmacy Comoridities better understand the effects of binge drinking on biological systems.

Genetics Acknowledgments Figure 4 Factors that contribute to disease processes associated with binge alcohol The authors are grateful for edito- drinking. For individuals who drink alcohol, factors such as type of alcohol, pattern rial support from Rebecca Gonzales of consumption, duration of alcohol misuse, and the age and diet of the drinker contribute to the incidence and severity of tissue injury. Another factor, polypharmacy, and grant support from the National particularly affects the older adult population, as multiple medications increase Institute on Alcohol Abuse and the potential for toxicity during an alcohol binge. Similarly, pre-existing comorbid Alcoholism (NIAAA) of the National conditions may predispose binge drinkers to accelerated tissue injury. Finally, genetic Institutes of Health (NIH) un- predisposition and environmental toxins are likely to be determining factors that affect der award number P60AA009803 the incidence and severity of tissue and organ injury. (LSUHSC-NO Comprehensive Alcohol–HIV/AIDS Research Center). e8 | Vol. 39, No. 1 Alcohol Research: Current Reviews Financial Disclosure wine, or spirits? BMJ. 1996;312(7033):731-736. 26. Qin Y, Hamilton JL, Bird MD, et al. Adipose PMID: 8605457. inflammation and macrophage infiltration after binge ethanol and burn injury. Alcohol Clin Exp Res. The authors declare that they have 13. Naimi TS, Brewer RD, Miller JW, et al. What do 2014;38(1):204-213. PMID: 23909743. no competing financial interests. binge drinkers drink? Implications for alcohol control policy. Am J Prev Med. 2007;33(3):188- 27. Reuben A. Alcohol and the liver. Curr Opin 193. PMID: 17826577. Gastroenterol. 2008;24(3):328-338. PMID: 18408461. References 14. Rao R. Endotoxemia and gut barrier dysfunction in . Hepatology. 28. National Institute on Alcohol Abuse and Alcoholism. 1. Lim SS, Vos T, Flaxman AD, et al. A comparative 2009;50(2):638-644. PMID: 19575462. 10th Special Report to the U.S. Congress on Alcohol risk assessment of burden of disease and injury 15. Bala S, Marcos M, Gattu A, et al. Acute binge and Health: Highlights From Current Research. attributable to 67 risk factors and risk factor clusters drinking increases serum endotoxin and bacterial Rockville, MD: U.S. Department of Health and Human in 21 regions, 1990–2010: A systematic analysis for DNA levels in healthy individuals. PloS One. Services; June 2000. the Global Burden of Disease Study 2010. Lancet. 2014;9(5):e96864. PMID: 24828436. 2012;380(9859):2224-2260. PMID: 23245609. 29. Beier JI, McClain CJ. Mechanisms and cell 16. Enomoto N, Ikejima K, Bradford BU, et al. Role signaling in alcoholic liver disease. Biol Chem. 2. World Health Organization. Global Status Report of Kupffer cells and gut-derived endotoxins in 2010;391(11):1249-1264. PMID: 20868231. on . Geneva, Switzerland: World alcoholic liver injury. J Gastroenterol Hepatol. Health Organization Press; 2011. 30. Gao B, Bataller R. Alcoholic liver disease: 2000;15(suppl 1):20-25. PMID: 10759216. Pathogenesis and new therapeutic targets. 3. Molina PE, Gardner JD, Souza-Smith FM, et al. 17. Bode C, Kugler V, Bode JC. Endotoxemia in patients Gastroenterology. 2011;141(5):1572-1585. Alcohol abuse: Critical pathophysiological processes with alcoholic and non-alcoholic cirrhosis and PMID: 21920463. and contribution to disease burden. Physiology in subjects with no evidence of chronic liver (Bethesda). 2014;29(3):203-215. PMID: 24789985. 31. Shukla SD, Velazquez J, French SW, et al. Emerging disease following acute alcohol excess. J Hepatol. role of epigenetics in the actions of alcohol. 4. Mokdad AH, Marks JS, Stroup DF, et al. Actual 1987;4(1):8-14. PMID: 3571935. Alcohol Clin Exp Res. 2008;32(9):1525-1534. causes of death in the , 2000. JAMA. PMID: 18616668. 2004;291(10):1238-1245. PMID: 15010446. 18. Mutlu EA, Gillevet PM, Rangwala H, et al. Colonic microbiome is altered in alcoholism. 32. Ki SH, Park O, Zheng M, et al. Interleukin-22 5. National Institute on Alcohol Abuse and Am J Physiol Gastrointest Liver Physiol. treatment ameliorates alcoholic liver injury in a Alcoholism. Drinking levels defined. https://www. 2012;302(9):G966-G978. PMID: 22241860. niaaa.nih.gov/alcohol-health/overview-alcohol- murine model of chronic-binge ethanol feeding: consumption/moderate-binge-drinking. Accessed 19. Canesso M, Lacerda N, Ferreira C, et al. Comparing Role of signal transducer and activator of October 26, 2017. the effects of acute alcohol consumption in transcription 3. Hepatology. 2010;52(4):1291-1300. germ-free and conventional mice: The role of the PMID: 20842630. 6. and Mental Health Services gut microbiota. BMC Microbiol. 2014;14:240. 33. Zaldivar Fujigaki JL, Arroyo Valerio AG, López Administration, Center for Behavioral Health Statistics PMID: 25223989. and Quality. Results From the 2015 National Alvarenga JC, et al. Alterations in activation, cytotoxic Survey on Drug Use and Health: Detailed Tables. 20. Schnabl B, Brenner DA. Interactions between capacity and trafficking profile of peripheral CD8 September 8, 2016. https://www.samhsa.gov/data/ the intestinal microbiome and liver diseases. T cells in young adult binge drinkers. PloS One. sites/default/files/NSDUH-DetTabs-2015/NSDUH- Gastroenterology. 2014;146(6):1513-1524. 2015;10(7):e0132521. PMID: 26151816. DetTabs-2015/NSDUH-DetTabs-2015.pdf. Accessed PMID: 24440671. 34. Åberg F, Helenius-Hietala J, Puukka P, et al. Binge October 26, 2017. 21. Rao RK, Seth A, Sheth P. Recent advances in drinking and the risk of liver events: A population- 7. Del Boca FK, Darkes J, Greenbaum PE, et al. Up close alcoholic liver disease I. Role of intestinal based cohort study. Liver Int. 2017;37(9):1373-1381. and personal: Temporal variability in the drinking permeability and endotoxemia in alcoholic liver PMID: 28276137. of individual college students during their first disease. Am J Physiol Gastrointest Liver Physiol. year. J Consult Clin Psychol. 2004;72(2):155-164. 2004;286(6):G881-G884. PMID: 15132946. 35. Samokhvalov AV, Rehm J, Roerecke M. Alcohol PMID: 15065951. consumption as a risk factor for acute and chronic 22. Zhong W, Zhou Z. Alterations of the gut pancreatitis: A systematic review and a series of 8. Sobell LC, Sobell MB. Timeline followback: A technique microbiome and metabolome in alcoholic liver meta-analyses. EBioMedicine. 2015;2(12):1996- for assessing self-reported alcohol consumption. In: disease. World J Gastrointest Pathophysiol. 2002. PMID: 26844279. Litten R, Allen Z, eds. Measuring Alcohol Consumption: 2014;5(4):514-522. PMID: 25400995. Psychosocial and Biochemical Methods. Totowa, NJ: 36. Deng L, Xue P, Huang L, et al. Binge drinking Humana; 1992:41-72. 23. Lowe PP, Gyongyosi B, Satishchandran aggravates the outcomes of first-attack severe A, et al. Alcohol-related changes in the acute pancreatitis. Pancreas. 2010;39(2):149-152. 9. Naimi TS, Nelson DE, Brewer RD. The intensity of binge intestinal microbiome influence neutrophil PMID: 19820420. alcohol consumption among U.S. adults. Am J Prev infiltration, inflammation and steatosis in Med. 2010;38(2):201-207. PMID: 20117577. early alcoholic hepatitis in mice. PloS One. 37. Ren Z, Yang F, Wang X, et al. Chronic plus binge 10. Liberale L, Bonaventura A, Montecucco F, et al. Impact 2017;12(3):e0174544. PMID: 28350851. ethanol exposure causes more severe pancreatic injury and inflammation.Toxicol Appl Pharmacol. of red wine consumption on cardiovascular health. 24. Souza-Smith FM, Ford SM Jr, Simon L, et al. 2016;308:11-19. PMID: 27538709. Curr Med Chem. 2017;24. PMID: 28521683. Repeated binge-like alcohol intoxication: Depot- 11. Mukamal KJ, Conigrave KM, Mittleman MA, et al. Roles specific adipose tissue immuno-metabolic 38. Apte MV, Wilson JS. Alcohol-induced pancreatic injury. of drinking pattern and type of alcohol consumed dysregulation. Shock. 2017;48(2):243-250. Best Pract Res Clin Gastroenterol. 2003;17(4):593- in coronary heart disease in men. N Engl J Med. PMID: 28125531. 612. PMID: 12828957. 2003;348(2):109-118. PMID: 12519921. 25. Fan AZ, Russell M, Naimi T, et al. Patterns of alcohol 39. Setiawan VW, Monroe K, Lugea A, et al. Uniting 12. Rimm EB, Klatsky A, Grobbee D, et al. Review of consumption and the metabolic syndrome. J and experimental disease models moderate alcohol consumption and reduced risk Clin Endocrinol Metab. 2008;93(10):3833-3838. for alcohol-related pancreatic disease. Alcohol Res. of coronary heart disease: Is the effect due to beer, PMID: 18628524. 2017;38(2):173-182. PMID: 28988572.

Binge Drinking’s Effects on the Body | e9 40. Kloner RA, Rezkalla SH. To drink or not to drink? That is of binge drinking. Alcohol Alcohol. 2013;48(2):131- 69. Muthukumar T, Jha V, Sud A, et al. Acute renal failure the question. Circulation. 2007;116(11):1306-1317. 137. PMID: 22878590. due to nontraumatic rhabdomyolysis following PMID: 17846344. binge drinking. Ren Fail. 1999;21(5):545-549. 55. Krenz M, Korthuis RJ. Moderate ethanol ingestion PMID: 10517000. 41. Potter JF, Watson RD, Skan W, et al. The pressor and and cardiovascular protection: From epidemiologic metabolic effects of alcohol in normotensive subjects. associations to cellular mechanisms. J Mol Cell 70. Hewitt SM, Winter RJ. Rhabdomyolysis following Hypertension. 1986;8(7):625-631. PMID: 3522422. Cardiol. 2012;52(1):93-104. PMID: 22041278. acute alcohol intoxication. J Accid Emerg Med. 1995;12(2):143-144. PMID: 7582413. 42. Rosito GA, Fuchs FD, Duncan BB. Dose-dependent 56. Matyas C, Varga ZV, Mukhopadhyay P, et al. Chronic biphasic effect of ethanol on 24-h blood pressure in plus binge ethanol feeding induces myocardial 71. Genthon A, Wilcox SR. Crush syndrome: A case normotensive subjects. Am J Hypertens. 1999;12(2 oxidative stress, mitochondrial and cardiovascular report and review of the literature. J Emerg Med. Pt 1):236-240. PMID: 10090355. dysfunction, and steatosis. Am J Physiol Heart 2014;46(2):313-319. PMID: 24199724. Circ Physiol. 2016;310(11):H1658-H1670. 43. Seppä K, Sillanaukee P. Binge drinking and 72. Ghacha R, Sinha AK. Acute renal failure due to PMID: 27106042. ambulatory blood pressure. Hypertension. rhabdomyolysis caused by hypokalemia. Saudi 1999;33(1):79-82. PMID: 9931085. 57. Kalaz EB, Evran B, Develi S, et al. Effect of binge J Kidney Dis Transpl. 2001;12(2):187-190. ethanol treatment on prooxidant-antioxidant balance 44. Klatsky AL, Friedman GD, Siegelaub AB, et al. Alcohol PMID: 18209373. in rat heart tissue. Pathophysiology. 2012;19(1):49- consumption and blood pressure: Kaiser-Permanente 73. Helfer JL, Goodlett CR, Greenough WT, et al. The 53. PMID: 22336135. Multiphasic Health Examination data. N Engl J Med. effects of exercise on adolescent hippocampal 1977;296(21):1194-1200. PMID: 854058. 58. Yeligar SM, Chen MM, Kovacs EJ, et al. Alcohol and neurogenesis in a rat model of binge alcohol lung injury and immunity. Alcohol. 2016;55:51-59. 45. Mori TA, Burke V, Beilin LJ, et al. Randomized exposure during the brain growth spurt. Brain Res. PMID: 27788778. controlled intervention of the effects of 2009;1294:1-11. PMID: 19647724. alcohol on blood pressure in premenopausal 59. Happel KI, Nelson S. Alcohol, immunosuppression, 74. Poulsen MB, Jakobsen J, Aagaard NK, et al. Motor women. Hypertension. 2015;66(3):517-523. and the lung. Proc Am Thorac Soc. 2005;2(5):428- performance during and following acute alcohol PMID: 26123682. 432. PMID: 16322595. intoxication in healthy non-alcoholic subjects. 46. Lewington S, Clarke R, Qizilbash N, et al. Age-specific 60. Molina PE, Katz PS, Souza-Smith F, et al. Alcohol’s Eur J Appl Physiol. 2007;101(4):513-523. relevance of usual blood pressure to vascular burden on immunity following burn, hemorrhagic PMID: 17717682. mortality: A meta-analysis of individual data for one shock, or traumatic brain injury. Alcohol Res. 75. Prentice C, Stannard SR, Barnes MJ. Effects of million adults in 61 prospective studies. Lancet. 2015;37(2):263-278. PMID: 26695749. heavy episodic drinking on physical performance 2002;360(9349):1903-1913. PMID: 12493255. 61. Shults JA, Curtis BJ, Chen MM, et al. Impaired in club level rugby union players. J Sci Med Sport. 47. Leong DP, Smyth A, Teo KK, et al. Patterns of alcohol respiratory function and heightened pulmonary 2015;18(3):268-271. PMID: 24820258. consumption and myocardial infarction risk: inflammation in episodic binge ethanol intoxication 76. Barnes MJ, Mündel T, Stannard SR. The effects Observations from 52 countries in the Interheart and burn injury. Alcohol. 2015;49(7):713-720. of acute alcohol consumption on recovery case-control study. Circulation. 2014;130(5):390- PMID: 26364264. from a simulated rugby match. J Sports Sci. 398. PMID: 24928682. 62. Shults JA, Curtis BJ, Boe DM, et al. Ethanol 2012;30(3):295-304. PMID: 22168345. 48. Marques-Vidal P, Arveiler D, Evans A, et al. Different intoxication prolongs post-burn pulmonary 77. Barnes MJ, Mündel T, Stannard SR. Acute alcohol alcohol drinking and blood pressure relationships inflammation: Role of alveolar macrophages. consumption aggravates the decline in muscle in France and Northern Ireland: The PRIME J Leukoc Biol. 2016;100(5):1037-1045. performance following strenuous eccentric study. Hypertension. 2001;38(6):1361-1366. PMID: 27531926. exercise. J Sci Med Sport. 2010;13(1):189-193. PMID: 11751718. 63. Bird MD, Kovacs EJ. Organ-specific inflammation PMID: 19230764. 49. Mukamal KJ, Maclure M, Muller JE, et al. Binge following acute ethanol and burn injury. J Leukoc 78. Levitt DE, Luk HY, Duplanty AA, et al. Effect of drinking and mortality after acute myocardial Biol. 2008;84(3):607-613. PMID: 18362209. alcohol after muscle-damaging resistance infarction. Circulation. 2005;112(25):3839-3845. 64. Sears BW, Volkmer D, Yong S, et al. Binge alcohol exercise on muscular performance recovery and PMID: 16365208. exposure modulates rodent expression of biomarkers inflammatory capacity in women.Eur J Appl Physiol. 50. Sundell L, Salomaa V, Vartiainen E, et al. Increased of the immunoinflammatory response to orthopaedic 2017;117(6):1195-1206. PMID: 28386694. stroke risk is related to a binge-drinking habit. Stroke. trauma. J Bone Joint Surg Am. 2011;93(8):739-749. 79. Andersen H, Aagaard NK, Jakobsen J, et al. Lower 2008;39(12):3179-3184. PMID: 18832741. PMID: 21508281. muscle endurance in patients with alcoholic liver 51. Wannamethee G, Shaper AG. Alcohol and sudden 65. Molina PE, Sulzer JK, Whitaker AM. Alcohol abuse and disease. Int J Rehabil Res. 2012;35(1):20-25. cardiac death. Br Heart J. 1992;68(5):443-448. the injured host: Dysregulation of counterregulatory PMID: 22027807. PMID: 1467026. mechanisms review. . 2013;39(3):240-249. Shock 80. Boekeloo BO, Novik MG, Bush E. Drinking to PMID: 23416555. 52. Conen D, Chae CU, Glynn RJ, et al. Risk of death get drunk among incoming freshmen college and cardiovascular events in initially healthy 66. Zhang P, Bagby GJ, Happel KI, et al. Alcohol abuse, students. Am J Health Educ. 2011;42(2):88-95. women with new-onset atrial fibrillation.JAMA . immunosuppression, and pulmonary infection. Curr PMID: 23440674. 2011;305(20):2080-2087. PMID: 21610240. Drug Abuse Rev. 2008;1(1):56-67. PMID: 19630706. 81. Hingson RW, Zha W, Weitzman ER. Magnitude 53. Mostofsky E, Chahal HS, Mukamal KJ, et al. Alcohol 67. Preedy VR, Ohlendieck K, Adachi J, et al. The of and trends in alcohol-related mortality and and immediate risk of cardiovascular events: importance of alcohol-induced muscle disease. morbidity among U.S. college students ages 18–24, A systematic review and dose-response meta- J Muscle Res Cell Motil. 2003;24(1):55-63. 1998–2005. J Stud Alcohol . July 2009;(suppl analysis. Circulation. 2016;133(10):979-987. PMID: 12953836. 16):12-20. PMID: 19538908. PMID: 26936862. 68. Fernández-Solà J, Preedy VR, Lang CH, et al. 82. Wechsler H, Kuo M. College students define binge 54. Gu L, Fink AM, Chowdhury SA, et al. Cardiovascular Molecular and cellular events in alcohol- drinking and estimate its prevalence: Results of a responses and differential changes in mitogen- induced muscle disease. Alcohol Clin Exp Res. national survey. J Am Coll Health. 2000;49(2):57- activated protein kinases following repeated episodes 2007;31(12):1953-1962. PMID: 18034690. 64. PMID: 11016129. e10 | Vol. 39, No. 1 Alcohol Research: Current Reviews 83. Koeltzow TE, White FJ. Behavioral 88. LaBrie JW, Hummer J, Kenney S, et al. Identifying 92. Smith KW, Gierski F, Andre J, et al. Altered white during withdrawal is associated with factors that increase the likelihood for alcohol- matter integrity in whole brain and segments decreased spontaneous activity of ventral induced blackouts in the prepartying context. of , in young social drinkers tegmental area dopamine . Behav Neurosci. Subst Use Misuse. 2011;46(8):992-1002. with binge drinking pattern. Addict Biol. 2003;117(4):860-865. PMID: 12931970. PMID: 21222521. 2017;22(2):490-501. PMID: 26687067.

84. Perry PJ, Argo TR, Barnett MJ, et al. The association 89. Morris LS, Dowell NG, Cercignani M, et al. 93. Crews FT, Vetreno RP, Broadwater MA, et al. of alcohol-induced blackouts and grayouts to Binge drinking differentially affects cortical Adolescent alcohol exposure persistently blood alcohol concentrations. J Forensic Sci. and subcortical microstructure. Addict Biol. impacts adult neurobiology and behavior. 2006;51(4):896-899. PMID: 16882236. 2018;23(1):403-411. PMID: 28105707. Pharmacol Rev. 2016;68(4):1074-1109. PMID: 27677720. 85. Hartzler B, Fromme K. Fragmentary and en bloc 90. Schweinsburg AD, McQueeny T, Nagel BJ, et blackouts: Similarity and distinction among al. A preliminary study of functional magnetic 94. Zahr NM, RohlfingT, Mayer D, et al. Transient episodes of alcohol-induced memory loss. J Stud resonance imaging response during verbal CNS responses to repeated binge ethanol Alcohol. 2003;64(4):547-550. PMID: 12921196. encoding among adolescent binge drinkers. treatment. Addict Biol. 2016;21(6):1199-1216. 86. White A, Hingson R. The burden of alcohol use: Alcohol. 2010;44(1):111-117. PMID: 20113879. PMID: 26283309. Excessive alcohol consumption and related 91. Squeglia LM, Schweinsburg AD, Pulido C, et al. 95. Guerri C, Pascual M. Mechanisms involved in consequences among college students. Alcohol Adolescent binge drinking linked to abnormal the neurotoxic, cognitive, and neurobehavioral Res. 2013;35(2):201-218. PMID: 24881329. spatial working memory brain activation: effects of alcohol consumption during 87. Goodwin DW. Alcohol amnesia. Addiction. Differential gender effects. Alcohol Clin Exp Res. adolescence. Alcohol. 2010;44(1):15-26. 1995;90(3):315-317. PMID: 7735016. 2011;35(10):1831-1841. PMID: 21762178. PMID: 20113871.

Binge Drinking’s Effects on the Body | e11