Medical comorbidity and alcohol dependence - Springer Link

Medical Comorbidity and Alcohol Dependence Paolo Mannelli, MD, and Chi Un Pae, MD

Corresponding author Paolo Mannelli, MD Duke University Medical Center, 2218 Elder Street, 2B, Durham, NC 27705, USA. E-mail: [email protected] Current Psychiatry Reports 2007, 9:217–224 Current Medicine Group LLC ISSN 1523-3812 Copyright © 2007 by Current Medicine Group LLC

Alcohol dependence (AD) and, more generally, alcohol use disorders (AUDs) predispose individuals to adverse consequences that extend beyond the expected damage from alcohol-direct toxicity. Research has shown that the relationship of alcohol use to health outcomes is complex, as is the etiology of AD, and that the individual and social costs of alcohol-related problems are increasing. We review advances in alcohol science that explore the role of alcohol consumption and patterns of drinking in a range of medically comorbid conditions. Although new knowledge can assist in the development of appropriate medical management strategies, AUDs account for an important percentage of the global burden of disease and require approaches that are not uniquely focused on the identification and treatment of AD.

Introduction Alcohol dependence (AD) is a chronic disease with complex genetic, psychosocial, and environmental underpinnings. The near-ubiquity of alcoholic beverages in human history has been associated with a constant perception of social and health problems caused by drinking. In the past 30 years, increased scientific attention to drinking problems has contributed to the collection of well-documented information on the long-term effects of chronic alcohol use/AD upon health. Recent research has contributed substantially to our understanding of the role of drinking in the manifestation of specific disorders and has shown that the relationship between alcohol consumption and health outcomes is multidimensional, as is the etiology of alcohol use disorders (AUDs). Alcohol has been causally related to more than 60 different medical conditions, and up to 40% of hospitalized patients receive treatment for complications of “alcohol misuse,” accounting

for more than 15% of their health care costs [1]. The Association of American Physicians estimates the annual US health care expenditure for alcohol-related medical problems to be $22.5 billion [2], out of $185 billion in costs for health care, lost productivity, and legal proceedings associated with alcohol consumption [3]. Of note, many of the physiologic changes resulting from AD can be stabilized or reversed if the patient stops drinking [4]. In our review of the evidence, we summarize the updates in methodology of evaluation of the effects of alcohol consumption and emphasize recent findings on medical implications of alcohol use. Although medical approaches are appropriate responses to AUD, it is necessary to complement them with public health interventions of prevention to effectively address the problem at the levels of communities and nations.

Alcohol Use and Health In high doses, alcohol is acutely toxic to most organ systems and can be the cause of medical emergencies. Table 1 summarizes acute medical conditions and the putative mechanism of alcohol-induced damage [5•]. However, not only volume of consumption, but various other dimensions of drinking have been shown to determine burden of disease [6]. Based upon 156 studies published from 1966 to 1998, Corrao et al. [7•] examined the relationship between levels of alcohol consumption and risk of diseases and injuries. Investigators found significantly increased risk for cancer among patients who drank alcohol and a direct correlation between daily amounts of alcohol intake and increasing risk. This direct correlation also was seen for essential hypertension; cirrhosis of the liver; chronic pancreatitis; and, to a certain extent, injuries and violence. However, a curvilinear effect was observed for coronary heart disease and ischemic stroke such that light or moderate drinking (25 to 50 g/d) conferred a protective effect, whereas heavy drinking was associated with significantly increased disease risk. These findings are summarized in Table 2. In the case of cardiovascular disorders, stroke, diabetes mellitus, and injuries, a crucial role in determining the outcome is

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Medicopsychiatric Disorders

Table 1. Medical conditions associated with AD and requiring acute care Medical condition

Mechanism

Neurological system AWS

Up-regulation of 3’5’-monophosphate in locus ceruleus, nucleus accumbens, and ventral tegmental area

Wernicke encephalopathy

Thiamine deficiency

Hepatic encephalopathy

Hypokalemia, metabolic alkalosis, GI hemorrhage

Cerebral infarction

Increase of high-density lipoprotein or lowering of BP

Intracranial hemorrhage

Increase of BP

Delirium tremens

Impairment of cerebral oxidative metabolism and multiple neurotransmitter abnormalities

Cardiovascular system Angina

Coronary vasospasm

Dysrhythmia

Myofibrillar necrosis, interstitial fibrosis, conduction failure

Cardiomyopathy

Myocyte loss, decrease of contractile proteins, calcium dysregulation

Acute MI

Coronary insufficiency

GI system Upper GI bleeding

Mucosal injury, formation of varices

Perforation Acute necrotizing pancreatitis

Acinar cell injuries, leakages of enzymes to interstitium

Respiratory system Acute respiratory distress syndrome Acute respiratory failure

Weakening of respiratory muscles, depression of mucociliary function, aspiration, decrease of normal respiratory defenses, immunosuppression

Respiratory infection Metabolic system Alcoholic ketoacidosis

Increased fatty acid breakdown, increased ketone bodies, impairment of glucose production

Electrolyte imbalance Hypoglycemia

Decrease of glycogenolysis, decreased glucose production

Acute renal failure

Azotemia, rhabdomyolysis, hepatorenal syndrome

Musculoskeletal system Myopathy Avascular necrosis on femoral hip AD—alcohol dependence; AWS—alcohol withdrawal syndrome; BP—blood pressure; GI—gastrointestinal; MI—myocardial infarction. (Adapted from Al-Sanouri et al. [5•].)

played by specific drinking patterns, especially irregular heavy drinking [8]. Although a wealth of data on medical complications from AUDs is available, many of the results are affected by shortcomings with respect to the epidemiology of use, in which exposure is often poorly measured, and studies typically have a shortage of people with patterns of irregular heavy drinking [9]. The National Institute on Alcohol Abuse and Alcoholism (NIAAA) has presented the results of the first wave of interviews from the National Epidemiologic Survey on Alcohol and Related Conditions. The available data on alcohol

consumption and medical conditions in the year 20012002 show a percentage of approximately 25% to 30% of health problems among 43,093 representative alcohol users, independent of the quantity consumed [10••]. The results of a second wave of interviews (2004-2005) from the same sample are eagerly awaited, as we should be able to learn more about how quantity of alcohol and duration of exposure influence the development of a disease [10••]. Given these premises, we briefly summarize the relationships between alcohol and medical outcome for significant groups of diseases and conditions that contribute

Medical Comorbidity and Alcohol Dependence Mannelli and Pae 219

Table 2. Pooled RRs and corresponding 95% CI for selected doses of alcohol consumption Pooled RR (and 95% CI) associated with alcohol intake 25 g/d

50 g/d

100 g/d

Essential hypertension

1.43 (1.33–1.53)

2.04 (1.77–2.35)

4.15 (3.13–5.52)

Coronary heart disease

0.81 (0.79–0.83)

0.87 (0.84–0.90)

1.13 (1.06–1.21)

Ischemic stroke

NS

NS

4.37 (2.28–8.37)

Hemorrhagic stroke

NS

1.82 (1.46–2.28)

4.70 (3.35–6.59)

Gastroduodenal ulcer Liver cirrhosis Chronic pancreatitis

NS

NS

NS

2.90 (2.71–3.09)

7.13 (6.35–8.00)

26.52 (22.26–31.59)

1.3 (1.16–1.54)

1.78 (1.34–2.36)

3.19 (1.82–5.59)

Injuries and violence

1.12 (1.06–1.18)

1.26 (1.13–1.40)

1.58 (1.27–1.95)

Oral cavity and pharynx

1.86 (1.76–1.96)

3.11 (2.85–3.39)

6.45 (5.76–7.24)

Esophagus

1.39 (1.36–1.42)

1.93 (1.85–2.00)

3.59 (3.34–3.87)

Larynx

1.43 (1.38–1.48)

2.02 (1.89–2.16)

3.86 (3.42–4.35)

Colon

1.05 (1.01–1.09)

1.10 (1.03–1.18)

1.21 (1.05–1.39)

Rectum

1.09 (1.08–1.12)

1.19 (1.14–1.24)

1.42 (1.30–1.55)

Liver

1.19 (1.12–1.27)

1.40 (1.25–1.56)

1.81 (1.50–2.19)

Breast

1.25 (1.20–1.29)

1.55 (1.44–1.67)

2.41 (2.07–2.80)

NS—not significant. (Adapted from Corrao et al. [7•].)

to the health harms from drinking, with particular attention paid to recent advances in our knowledge of the association. Clinical definitions and measures of alcohol consumption that are used throughout this report are summarized in Table 3.

Central Nervous System (CNS) Alcohol is a CNS depressant that causes many different acute and chronic detrimental health effects. Acute effects of alcohol intoxication include impairment in judgment and coordination (associated with trauma), blackouts, temporary anterograde amnesia, alterations in sleep stages, and sleep apnea from relaxation in pharyngeal muscles. Potential chronic effects are numerous and often involve cognitive impairment and encephalopathy that may be severe in chronic alcohol users. Peripheral neuropathy and irreversible dementia are two consequences that can develop in chronic alcoholics. Abrupt discontinuation of alcohol intake as part of a dependence disorder can also induce complications of the CNS and other systems [4,11]. Typical CNS sequelae of alcohol use and discontinuation are included in the clinical syndromes described subsequently.

Alcohol withdrawal syndrome (AWS) AWS may follow abrupt cessation of drinking after the development of dependence, with onset happening within hours of last drink and peak occurring within 24 to 48 hours. Symptoms and signs consist of

a spectrum of clinical manifestations such as cloudy sensorium, autonomic instabilities, anxiety, agitation, seizures, and even psychotic manifestations with mild to extremely severe intensity that can lead to death [12]. In an effort to elucidate the pathophysiology of the syndrome, a significant association between AWS and volume of daily alcohol consumption and craving intensity was found, which suggests the involvement of mechanisms of volume regulation, such as the arginine-vasopressin system, in the neurobiology of alcohol craving and AWS [13]. The National Trauma Registry of the American College of Surgeons has conducted a retrospective review of 6431 charts from July 1999 to February 2004. Patients presenting with AWS had more severe medical complications such as respiratory failure, pneumonia, urinary tract infection, sepsis, tracheostomy, and endoscopic gastrostomy; more hospital stays; and more global medical costs compared with non-AWS patients [14•]. This study highlights the importance of identifying patients at risk in order to establish AWS prophylaxis. A number of investigations suggest the utility of combining common biological markers of alcohol use with the score on the Alcohol Use Disorders Identification Test (AUDIT) [15••] to enhance the results of screening for AUDs and to identify patients at risk of developing AWS. Two abnormal results within the “panel of four (mean corpuscular volume [MCV], aspartate aminotransferase [AST], alanine aminotransferase [ALT], and H glutamyltransferase [GGT] carbohydrate-deficient transferrin [CDT]),” in combina-

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Table 3. Terms and definitions pertaining to alcohol use Term Standard drink (~ 12 g of alcohol) Moderate drinking

Definition ~ 12 oz of beer or ~ 5 oz of wine or ~ 0.5 oz of 80-proof liquor ≤ 2 drinks/d (men), ≤ 1 drink/d (women or adults aged ≥ 65 years)

Moderate to heavy drinking

3–4 drinks/d (men), 2–3 drinks/d (women)

Maximum daily drinking limit

3–4 drinks/d (men), 2–3 drinks/d (women)

Heavy drinking

≥ 5 drinks/d (men), ≥ 4 drinks/d (women), 2 times/wk for 1 month

Binge drinking

≥ 5 drinks on a single occasion or drinking behaviors that raise an individual’s BAC to ≥ 0.08%

BAC—blood alcohol concentration; oz—ounces. (Data from National Institute on Alcohol Abuse and Alcoholism [10••] and O’Connor et al. [32].)

tion with above-cutoff AUDIT scores provide the optimal balance between maintaining sensitivity and increasing the predictive value of the test in identifying patients who may develop withdrawal symptoms (sensitivity 70.6%, specificity 98.8%, positive predictive value 54.5%, negative predictive value 99.4%) [16].

eventually reaches full HE status [21]. The prevalence of SHEs among patients with cirrhosis varies between 30% and 84%, depending on the modality of application of the diagnostic criteria [22].

Gastrointestinal Hepatic encephalopathy (HE)

Hepatic disease

Although there is debate surrounding the mechanisms underlying this syndrome, it can be defined as a broad spectrum of neuropsychiatric manifestations usually affecting patients with liver failure and/or a portal-systemic bypass, possibly as complications of AD (also see “Hepatic disease”) [17]. Since 2002, a new nomenclature of HE classifies HE as encephalopathy type A (associated with acute liver failure), type B (associated with portal-systemic bypass), and type C (associated with liver cirrhosis). HE type A is characterized by a rapid development to coma, cerebral edema, and a poor short-term prognosis in which the patient needs the most urgent care and, sometimes, liver transplant [18]. There are several suggested pathophysiologic mechanisms for HE, but there is a general consensus on the primary role of gut-derived toxins such as ammonia. Precipitating factors for HE include constipation (delayed transit), gastrointestinal bleeding (gut protein), high-protein diet, electrolyte abnormalities (hypokalemia, hyperazotemia), medications (sedatives and narcotics that slow intestinal transit), and infections (protein catabolism, cytokines). HE usually is reversible with the correction of the risk factors [19]. However, in large retrospective studies, HE is found to be a strong independent predictor of mortality as well (hazard ratio = 2.8, P < 0.0001) [20]. Subclinical forms of HE (SHEs), showing some symptoms of HE but with grossly normal mental and neurological status, represent an important clinical category. Patients with SHEs usually demonstrate abnormal behaviors in daily life, such as circadian rhythm, mood changes, and mild cognitive impairment, that may lead to erroneous diagnoses [21]. This condition slowly worsens with the progression of the underlying liver disease and

Alcohol is directly toxic to the liver. However, the level of susceptibility and the severity of liver disease vary among drinkers. Influencing factors include genetics, dietary habits, gender, body mass index, weight, type of beverage and drinking duration, and presence of other liver diseases such as hepatitis [23]. The prevalent types of alcoholic liver diseases are fatty liver, alcoholic hepatitis, and cirrhosis. As people continue to drink, these frequently progress from fatty liver to hepatitis to cirrhosis, although all three distinct disorders can occur simultaneously [13,23,24]. Fatty liver develops in approximately 90% to 100% of heavy drinkers, and approximately 30% of the patients present with alcoholic hepatitis on liver biopsy [25]. There is a dose-dependent increase in the RR of alcoholic liver disease for both men and women, with the steepest increase among women. In large, prospective cohort studies, the minimum alcohol intake associated with a significant increase in the prevalence of liver disease was 30 g/d in both sexes [26]. However, a recent study conducted in Eastern Asiatic populations demonstrated that smaller alcohol quantities and a relatively short exposition (20 g/d and 5 years for men) can account for an increased prevalence of liver disease, with a greater risk coming from liquors or multiple beverages and drinking outside meals [27]. This is to remark on the influence that race and ethnicity can exert on susceptibility to disease. The amount of alcohol consumed and the duration of consumption are strongly associated with the development of hepatic cirrhosis, the most serious form of alcoholic liver disease. In alcoholics who stop drinking, the 5-year survival rate is approximately 90% [23,24].

Other disorders


Alcohol affects many other gastrointestinal organs. A few of the most common or severe disorders are malabsorption syndromes and electrolyte disorders, esophagitis or gastritis, and various types of gastrointestinal cancers. For instance, alcohol consumption may account for as many as 72.4% of esophageal squamous cell carcinomas [4,28]. Approximately 30% of acute pancreatitis cases in the United States are alcohol related, and a positive history of chronic alcohol consumption is found in 60% to 90% of pancreatitis patients [29]. The pathogenesis of alcoholic pancreatitis remains obscure, although alcohol consumption may predominate over other factors such as smoking. Whether or not heavy alcohol consumption is directly associated with the development of pancreatic cancer, chronic alcohol intake may promote carcinogenesis by increasing the risk of diabetes mellitus or chronic pancreatitis [30].

Cardiac and Vascular A comprehensive meta-analysis on average volume of alcohol consumption and coronary heart disease (CHD) found a J-shaped curve [31]. Compared with nondrinking, low to moderate consumption of alcohol is associated with lower CHD incidence and mortality, the lowest risk being found at 20 g/d (fewer than two drinks). For higher average volume of alcohol intake, the risk reverses, and consuming three or more drinks per day also results in a dose-dependent increase in blood pressure, contributing to the development of mild to moderate hypertension. Consuming greater than 90 to 100 g of alcohol per day damages the heart and increases the risk of sudden cardiac death, especially in patients with CHD. Alcoholic cardiomyopathy may develop in patients with a long history of alcoholism [4,28]. It is estimated that the equivalent of six drinks daily for longer than 10 years would significantly increase the risk of cardiomyopathy [32]. Several studies confirming the cardioprotective effect of regular light to moderate drinking found an increased risk for major coronary events in drinkers with an episodic heavy drinking pattern compared with abstainers, even when the overall volume of drinking was low [33]. Another drinking pattern that seems to have a role in the cardiovascular protective effect is drinking with meals [34]. In addition to its effect on CHD, an irregular pattern of heavy drinking occasions appears to be related to other types of cardiac and vascular problems, such as stroke or sudden cardiac death [28,35]. This association is consistent with the increased clotting, lowered threshold for ventricular fibrillation, and elevation of low-density lipoproteins that occur after heavy drinking. Although the association between alcohol consumption and ventricular arrhythmia has not been quantified, 30% to 60% of patients with atrial fibrillation show a history of alcohol consumption [32]. An attempt to control for the influence of lifestyle on the development of cardiac and vascular disease associated with alcohol consumption was made in the evaluation of the inci-

dence of cases of myocardial infarction (MI), fatal CHD, and stroke in more than 50,000 participants in the Health Professionals Follow-up Study between 1986 and 2002. Among 8800 individuals reporting healthy lifestyle, moderate alcohol consumption was still associated with a decreased risk for MI, and there was a significantly lower risk of death due to CHD [36,37]. However, in the same population, the risk of both hemorrhagic stroke and ischemic stroke appeared to increase with heavy drinking (> 60 g/d) [37].

Bone, Musculature, and Metabolic Alcoholic myopathy may develop in 50% to 75% of alcoholics. Skeletal muscle weakness may improve with abstinence. The majority of research involving the effects of alcohol on bone supports the premise that large quantities of alcohol are detrimental to bone health. Alcohol appears to act on the skeleton both directly (by reducing bone formation and decreasing osteoblast proliferation) and indirectly (by altering the activity of parathyroid hormone, calcitonin, and vitamin D metabolites). Alcoholics are at an increased risk for osteopenia, fractures, and osteonecrosis [4,28]. Common metabolic derangements that occur in patients with acute intoxication, withdrawal, and chronic alcohol exposure include hypokalemia, hypomagnesemia, hypophosphatemia, hypoglycemia, ketoacidosis, and lactic acidosis. These conditions generally are multifactorial and can be life threatening. All can be reversed with intervention and abstinence [4,28].

Head and Neck Acetaldehyde, the primary metabolic product of ethanol, has mutagenic properties, although animal studies show that pure ethanol itself is not mutagenic, clastogenic, or carcinogenic [38]. Although the carcinogenic effects of alcohol have not been fully elucidated, alcohol intake may increase the susceptibility to carcinogens and cell proliferation in the mucosa, resulting in genetic changes with the development of dysplasia, leukoplakia, and carcinoma [39]. A dose-effect relationship between alcohol consumption and incidence of head and neck cancers is suggested, with a maximum RR for hypopharyngeal carcinoma [40]. A study examining 15,117 Danish men and 13,063 women followed for approximately 13 years confirmed that moderate intake of beer or liquor is sufficient to significantly increase the risk of oropharyngeal and esophageal cancer, with a 12-fold risk in heavy drinkers (s21 drinks/d) compared with nondrinkers [41]. Moderate wine intake was not associated with such a risk in the same population.

Breast Cancer Meta-analyses have shown a linear increase of risk of breast cancer parallel to average volume of consumption, ranging from 10 g/d of pure alcohol increasing the risk

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of breast cancer by 9% to 30 to 60 g/d associated with a risk of 41% [42]. Estrogen replacement therapy combined with alcohol use in postmenopausal women magnifies such risk [43]. Largely driven by these findings, the role of estrogen and its metabolism as one candidate for a causal pathway is being studied. A role for genetic polymorphisms in the association between alcohol and breast cancer also has been suggested [44].

Alcohol and Pregnancy Prenatal alcohol exposure not only seriously harms the fetus but also can induce behavioral problems in adolescence or adulthood. A follow-up study of individuals exposed to alcohol in utero found that 49% of adolescents and adults had repeatedly displayed inappropriate sexual behavior [45]. These results suggest that the effects of prenatal exposure to alcohol may perpetrate persistent impairments in response inhibition, memory, and executive functions that can be associated with future impulse control problems. Further research supports the existence of chronic effects of prenatal exposure to alcohol on executive functions, social skill development, and related neuropsychological defects [46].

death in the United States [51,52]. Reports from epidemiologic studies and the US Coast Guard indicate that alcohol use is involved in 10% to 30% of fatal general aviation crashes and 60% of boating fatalities [53].

Risky behaviors: the HIV example The subjective experience of alcohol effects include reduced fear and anxiety about the social, physical, or legal consequences of one’s actions, resulting in increased risk-taking and aggressive behavior in some drinkers, especially those with impulse control disorders. This is associated with biological findings linking alcohol, serotonin pathways, H-aminobutyric acid brain receptors, disinhibition, and aggression and justifies concerns about the spreading of HIV through sexual risk behaviors, especially in subjects with other comorbid psychiatric conditions [54,55]. In addition, the Multicenter AIDS Cohort Study and the Women’s Interagency HIV Study have shown that higher alcohol use is associated with significantly increased risk for mortality in HIV-positive individuals [56]. Chronic alcohol administration induces increased viral load and accelerated significant and early nutritional, metabolic, and immunologic alterations in HIV-positive animals [57], but the identification of direct toxic effects and the translation of such effects to humans require further investigation.

Fetal alcohol syndrome (FAS) FAS occurs in women who drink during pregnancy and affects three of every 1000 infants. The disorder is believed to present on a continuum, with less severe symptoms manifesting as developmental delays. Rates of less pronounced FAS remain unknown [47]. Fetal brain exposure to alcohol affects development of the hippocampus, frontal lobes, corpus callosum, and basal ganglia, which in turn may be responsible for symptoms associated with FAS [4].

Violent Injury and Risk-taking Behaviors Alcohol consumption has been linked to perpetration of violent crimes in the United States in up to 86% of cases, assault in up to 37% of cases, robbery 72%, and sexual offenses 60%, although the relation might not always be casual [48,49]. These findings indicate that men who reported having consumed alcohol prior to an injury incident were at 43% increased risk for subsequent violent injury.

Accident-related injuries The association between alcohol use and motor vehicle accident injury or fatality is well documented. The NIAAA reported that in 2002, 30.5% of total traffic crash fatalities were alcohol related [50]. According to the National Highway Traffic Safety Administration, 7% of all traffic accidents in 2003 were alcohol related. Alcoholrelated traffic fatalities totaled 17,013 in 2003, or 40% of fatal crashes in the United States, making alcohol-related traffic fatalities the leading cause of accidental vehicular

Conclusions The knowledge on the wide array of sequelae of alcohol use leads us to broaden the concept of medical treatment of comorbid disorders to include interventions on a complex of social and economic factors that influence the global burden of disease. Average volume of alcohol consumption and predominant patterns of drinking that are used to calculate the global burden of disease attributable to alcohol can be heavily influenced by the given social context [58]. In particular, drinking patterns are represented in terms of a country-specific hazardous drinking score composed of several indicators of heavy drinking occasions plus the frequency of drinking in public places and not drinking with meals [58]. The effect of alcohol varies greatly by region, from approximately 1% of the burden of disease in the poorest developing countries with low consumption to 12% in formerly socialist countries. Overall, 4% of the global burden of disease is attributable to alcohol. Thus, alcohol accounts for approximately as much of the burden of disease globally as tobacco (4.1%) and is surpassed only by the burdens caused by underweight (9.5%), unsafe sex (6.3%), and high blood pressure (4.4%) [59,60]. New knowledge can assist us in developing more appropriate management strategies for those affected by medical complications of alcohol use. However, in order to perform effective interventions, it is important to look beyond the frame of AD that has tended to dominate the


concerns of alcohol-related research and treatment until the recent past.

Acknowledgments The authors wish to thank Neena Ajwani for her editorial and research efforts. Neither author has a possible conflict of interest, financial or otherwise.

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