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Home , Alcohol abuse, Alcohol and health

Medical Consequences of Abuse

Studies have shown that long-term produces serious, harmful effects on a variety of the body’s organ systems. Parts of the human body most affected include the and the immune, cardiovascular, and skeletal systems. Current research has examined some of these effects in an effort to better understand the medical consequences of alcohol use and abuse and to ultimately develop more effective treatments for responding to alcohol-induced bodily damage. This article discusses some of those findings. KEY WO R D S : chronic AODE (effects of AOD [alcohol or other drug] use, abuse, or dependence); alcoholic liver disorder; ; cardiovascular system; bone; breast; ; ; heart disorder; cardiac

ong-term alcohol abuse is known to se r vat i v ely estimated at more than 2 sp r ead of localized or infection exe r t harmful effects on a number million. Women, compared with men, while mobilizing the defense mecha- Lof the body’s organ systems. Those de v elop and alcoholic nisms of the immune system. An impor- most affected by alcohol abuse include after fewer years of drinking tant aspect of liver inflammation is the the liver and the immune, cardi o vas c u - and from ingesting smaller daily amounts pr oduction of chemical messengers called la r , and skeletal systems. Many of the of alcohol. Rat studies confirm grea t e r cytokines, which help regulate the inflam- mechanisms invol v ed in alcohol’s effects li v er damage in females than in males at ma t o r y pr ocess. Cytokines attract and on these systems are not yet completely the same alcohol concentration ac t i v ate cells of the immune system, pro- understood. Consequently, recent res e a rc h (B AC ) . mote scar formation, and stimulate the has examined some of alcohol’s medical Th e r e are three forms of ALD: fatty pr oduction of additional chemical messen- consequences in an effort to increa s e li ve r , which is usually rev ersible with ge r s , including more cytokines. Howeve r , understanding and develop approp r i a t e ; alcoholic hepatitis, charac- if the increased levels of cytokines do not and effective trea t m e n t s . te r i z ed by persistent liver inflammation; subsequently return to normal, they can and cirrhosis, characterized by prog re s - cause chronic inflammation, leading to si v e scarring of liver tissue. A person can cell injury or cell death. Alcoholic ha v e more than one type of liver disease. Cytokine production can be stimu- Patients with both cirrhosis and alcoholic lated by endotoxin, a substance derived The liver is a vital organ invol v ed in hepatitis have a death rate of more than fr om the cell walls of certain bacteria pr ocessing fats, , proteins, and 60 percent over a 4-year period, with that reside in the human intestine. Hea v y vitamins and in regulating blood clot- most deaths occurring within the first alcohol consumption can increase the ting. It plays a central role in the body’s 12 months of diagnosis. passage of endotoxin through the intesti- defenses, filtering toxins and microb e s The major problem in devel o p i n g nal wall into the bloodstream. Spe c i a l i ze d fr om the blood and marshaling an ne w therapies for ALD has been a lack immune system cells (i.e., Kupffer cells) array of responses to trauma, stress, of understanding of the mechanisms for in the liver respond to blood-borne or inflammation. li v er injury. Howeve r , much has been en d o t o xin by producing inflammatory Although the liver is capable of reg e n - learned recently as a result of better cytokines. These cytokines furth e r er a t i o n and rep a i r , sever e liver disease technology and advances in res e a rc h . in c r ease gut permeability, perpetuating can be life threatening. Long-term, a destruc t i v e cycl e . heavy alcohol use is the leading cause The Process of Inflammation Another stimulus for exce s s i v e of illness and death from liver disease cytokine production is the generation in the . The number of Long-term alcohol consumption has of rea c t i v e oxygen species (ROS), toxi c persons with been shown to prolong the natural by- p r oducts of alcohol in (ALD), which ranges in severity from in f l a m m a t o r y responses of the liver . the liver . Nor m a l l y , ROS are quickly fatty liver to end-stage cirrhosis, is con- Inflammation functions to prev ent the in a c t i v ated by antioxidants, prot e c t i v e

Vol. 24, No. 1, 2000 27 molecules such as glutathione and ar e at high risk of having HCV, the lead- Cur r ent res e a r ch is examining the effects vi t a mins A and E. Howeve r , if these ing cause of liver transplantation in the of heavy drinking on the immune system. defenses are impaired or if there is an United States (National Institute on over p r oduction of ROS, the result can Alcohol Abuse and [NIAAA] How the Immune System Works be destruction of cell components and 1998). Findings indicate that patients ev entual cell death. with ALD who are HCV positive have The body’s first line of defense against Persistent liver inflammation is mo r e sever e liver disease and are you n g e r disease is inflammation, as described characteristic of alcoholic hepatitis and than HCV-n e g a t i v e patients (NIAAA ea r l i e r . Inflammation is a nonspecific usually precedes alcoholic cirrhosis. 1998). This increase in disease may ref l e c t response, directed against all sources of The hallmark of cirrhosis is cytokine- im p a i r ed immune function (i.e., immun- damage. When nonspecific defenses are induced scarring that distorts the liver ’s odeficiency) caused by alcohol abuse. br eached, an array of specific immune internal struc t u r e and impairs its func- Alcohol abusers may be at increa s e d responses (see table) come into play. tion. Imbalances in cytokine interac- risk compared with nonabusers for infec- Specific immune responses may be tions impair the normal regeneration of tion with human immunodeficiency virus br oadly classified as either cell-mediated tissue that typically follows liver injury. (H I V ) from risky sex practices while or humoral. Cell-mediated immunity in t o xicated. Res e a r chers also are inves t i - in vo l v es direct contact between immune Preventing Alcoholic Liver Injury gating whether alcohol consumption system cells and target cells (e.g., bacte- itself may increase susceptibility to HIV ria). Humoral immunity is provided by Res e a r chers have devised several strate- infection or hasten the prog r ession from antibodies that circulate in the blood gies to prev ent or minimize alcoholic HIV infection to full-blown AIDS. and lymph. Antibodies are specialized li v er damage. In experiments using rats, In addition, some alcohol-rel a t e d pr oteins designed to rec o g n i z e and dis- alcohol-induced liver injury has been organ damage, as in ALD, may res u l t able specific microoganisms or toxi c lessened by suppressing endotoxi n - in part from immune system over a c t i v i t y substances. Antibodies that persist in pr oducing intestinal bacteria (e.g., in which the immune system attacks the the bloodstream may confer long-term th r ough the use of antibiotics); admin- bo d y ’s own tissues (i.e., autoimmunity). immunity to a given disease. istering substances that selectivel y de s t r oy Kupffer cells or that inhibit the generation of ROS; and feeding anti- bodies that neutralize specific cytokines. Mediators of the Immune Response Experiments with a soybean extract, po l y enylphosphatidylcholine (PPC), Immune Response Function sh o wed that it could prev ent fibros i s and cirrhosis in alcohol-fed baboons. It also reduces the formation of scar tissue Humoral and may possess antioxidant prop e rt i e s Antibody A specialized protein that recognizes and disables specific as well. A study conducted by the U.S. microorganisms or toxic substances. When persisting in Dep a r tment of Veterans Affairs is cur- the bloodstream, it may help confer long-term immunity rently evaluating the effects of PPC in against a specific disease. humans with early ALD. Therapy with S-adenosyl-l-methionine (SAM) may Cell-Mediated lessen the depletion of the antioxi d a n t glutathione in liver cells. Choline and Phagocyte A specialized cell that engulfs invading microorganisms methionine, dietary factors related to and cell debris through a process known as phagocytosis. SAM, may help protect against endo- Macrophage A type of phagocyte that is the first to be activated during to xin-induced liver injury in rats. ph a g o cytosis. It resides in tissues and organs throughout the body. Neutrophil A type of phagocyte that aids in the destruction of invading Alcohol’s Effects microorganisms, in part by releasing toxic compounds on the Immune System known as (ROS). Together with monocytes, neutrophils are commonly referred to as white For 200 years physicians have observed blood cells. that exce s s i v e alcohol consumption can Monocyte A type of cell that is responsible for determining the “for- lead to increased illness and death from eignness” of an invading agent and then presenting such infectious diseases. Alcohol abusers suffer agents to other cells for destruction. Monocytes release fr om increased susceptibility to bacterial ROS to aid in the destruction process. They are also pneumonia, pulmonary , and referred to as white blood cells. hepatitis C (HCV). Patients with ALD

28 Alcohol Research & Medical Consequences of Alcohol Abuse

Phagocytes are specialized cells that tion by isolated lung macrophages after Coronary Heart Disease engulf invading microorganisms and challenge with TB organisms. The blood that nourishes the heart mus- cell debris through a process called phago- cy t o s i s . The first phagocytes to be acti- cl e is deliver ed through the coron a r y vated are macrophages, which reside in Therapeutic Measures ar teries. Manifestations of CHD range fr om episodic chest pain to sudden tissues and organs throughout the body. Some proposed therapies include admin- White blood cells infiltrate the area , death. Hea r t attacks, the most com- istration of such substances as antibod- mon serious manifestation of CHD, with neutrophils (a type of phagocyte) ies against endotoxin or against specific being the first to arrive, followed by ar e usually triggered by the formation monocytes. Monocytes are one of the cytokines, substances that would absorb of a blood clot within a coron a r y arte r y types of cells that initially determine th e ex cess cytokines or inhibit their func- al r eady narrowed by deposits of choles- “fo re i g n n e s s ” of an invading agent an d tion, and drugs that have a widesprea d te r ol and other fatty substances. The pr esent it to other cells, which res p o n d by effect (e.g., decreasing the permeability resulting ischemia reduces the heart’s pr oducing appropriate cytokines. of the intestinal wall to the passage of pumping ability, often leading to per- Various immune cells release chemical en d o t o xin). Administration of growt h manent disability or death. messengers to attract more cells, and and related chemical messen- With few exceptions, worldwide epidemiologic data demonstrate a 20- within neutrophils and macrophages, the gers has been shown to improve some, to xic oxygen-containing compounds to 40-percent lower CHD incidence but not all, measures of immune func- among drinkers compared with non- ROS destroy phagocytosed microo r g a n - tion in rats. isms. Excess ROS, howeve r , can damage drinkers. Heavy drinkers have an li v er cells. in c r eased risk of death from heart dis- Th r oughout the immune res p o n s e , ease. Howeve r , moderate drinkers exhibit Alcohol’s Effects on the lo wer rates of CHD-related morta l i t y cytokines continue their reg u l a t o r y Cardiovascular System functions. They include tumor necros i s than both heavy drinkers and abstainers. factor (TNF) and a family of both This is confirmed by studies in which in f l a m m a t o r y and anti-inflammatory Ch r onic heavy drinking is a leading pa r ticipants wer e intervi e wed about substances called interleukins. cause of cardi o vascular illnesses such as their drinking habits and life styles before de g e n e r a t i v e disease of heart muscle the onset of disease. Such studies— (c a rd i o m y opathy); disorders associated rep r esenting a total population of more How Alcohol Affects with decreased blood supply to the heart than 1 million men and women of dif- the Immune System muscle (coron a r y heart disease [CHD]); fe r ent ethnicities followed for up to 24 Both chronic and acute alcohol admin- high blood pres s u r e; heart rhythm disor- years—confirm an association betwee n istration can produce the loss of var i o u s ders (); and strok e . moderate drinking and lower CHD types of immune responses in experimen- risk. Howeve r , this association does not ta l animals. Administration of alcohol necessarily mean that alcohol itself is concentrations similar to those seen in Alcoholic Cardiomyopathy the cause of the lower risk. In addition, different epidemiologic binge drinkers impairs the function of Long-term heavy drinking can cause cu l t u r ed human monocytes and can studies apply the term “mo d e r a t e the heart to become enlarged and lose temporarily reduce the numbers and dr i n k i n g ” to a wide range of consump- activity of immune cells in mice. Alcohol some of its ability to contract, a condi- tion levels, sometimes more than the inhibits neutrophil migration in humans tion known as alcoholic cardi o m yo p a - amount defined by the Die t a r y Gui d e l i n e s and in experimental animals. Howeve r , th y . These symptoms include shortn e s s for Americans as moderate: two or an infiltration of neutrophils into the of breath and an insufficient blood flow fe wer standard drinks per day for men li v er is observed in alcoholic hepatitis. to the rest of the body. Women may and one or less per day for women. In Experiments with alcohol-fed rats showed ha v e a greater risk than men of devel - any case, the apparent benefits of mod- that their neutrophils engulfed bacteria oping alcoholic cardi o m yo p a t h y . The erate drinking on CHD mortality are efficiently but did not kill all strains of condition may be at least parti a l l y offset at higher drinking levels throu g h pneumonia-causing bacteria with nor- rev ersible with abstinence. in c r easing risk of death from other mal effectiven e s s . Al c o h o l ’s toxic effects on heart muscle al c o h o l - r elated causes. Res e a r ch has suggested several possi- Although inflammatory cytokine lev- may be mediated by increased ROS el s in c r ease in ALD, endotoxi n - i n d u c e d ble mechanisms by which alcohol may se c r etion of inflammatory cytokines in le v els and decreased antioxidant enzyme pr otect against CHD. For example, the lung may decrease in alcohol-fed ac t i v i t y . Another recent study found alcohol inhibits the deposition of fatty animals as well as in human al c o h o l i c s , that alcohol may decrease the sensitiv- substances within the coron a r y arte r i e s potentially increasing susceptibility to ity of heart muscle to chemical messen- of mice and also may inhibit the for- pneumonia. Acute administration of gers from nerve cells that regulate heart mation of blood clots within alrea d y alcohol to rats reduced ROS prod u c - muscle metabolism and contraction. na r r owed coron a r y arte r i e s .

Vol. 24, No. 1, 2000 29 Epidemiologic data and results of consumption and risk for bone fracture. can apparently be rev ersed by abstinence. studies on isolated animal hearts sug- In addition to increased risk of acciden- The skeletal consequences of alcohol gest that moderate alcohol consump- ta l in j u r y through alcohol-induced intake may be especially harmful during tion also may lower CHD mortality by impairment of gait and balance, alcoholics adolescence, when the rapid skeletal im p r oving survi v al after a heart attack. also may suffer from a generalized gr owth ultimately responsible for achiev- Fur ther studies are needed to confirm de c r ease in bone mass, making their in g peak bone mass occurs. By limiting this effect and to determine its applica- bones more fragile. Heavy drinking may peak bone mass attainment, the risk of bility in humans. de v eloping osteoporosis later in life may increase and its onset hastened. Alcohol and Blood Pressure Int o xication can Potential Mechanisms of Alcohol- An association between heavy alcohol cause certa i n types Induced Bone Disease consumption and increased blood pres - su r e has been observed in more than 60 of arrhythmia in Long-term consumption of alcohol dis- studies in diverse cultures and populations. rupts the processes of bone growth and The effects of moderate alcohol con- both alcoholics bone tissue rep a i r . A decrease in bone su m p t i o n on blood pres s u r e are unclear. and otherwise de n s i t y , as well as an increased risk of bone fracture, may result. These effects Arrhythmias healthy persons. of alcohol on bone may occur direc t l y , with alcohol itself interfering with bone The heart’s ability to function effectivel y metabolism, or indirec t l y , with alcohol depends on reg u l a r , synchronous con- lead to osteoporosis, characterized by exe r ting its effects through a third party , traction of the heart muscle. Hea v y se ve r e back pain, spinal deformity, and such as . The female rep r o- drinking can disrupt the heart rhythm in c r eased risk of wrist and hip fractures , du c t i v e hormone estrogen appears to both acutely (during an episode of although some recent studies suggest affect bone metabolism, although its drinking) and chronically (due to long- that moderate alcohol consumption role with respect to alcohol consump- term use). Int o xication can cause certa i n may protect against osteoporos i s . tion is uncerta i n . types of arrhythmia in both alcoholics A number of res e a r chers have noted and otherwise healthy persons. The Alcohol and Skeletal Development that alcohol can reduce osteoblast for- de v elopment of arrhythmias with binge mation. Alcohol can inhibit osteoblast drinking—a condition seen most fre- Bone growth and remodeling during pr oliferation in culture at concentrations quently around the holidays—is known childhood and adolescence invol v es the well within the drinking level observed as “holiday heart syndrom e . ” co o r dinated activity of two types of in alcoholics. A concentration of alco- Sudden death attributable to arrhyth- cells: (1) osteoclasts, which break down hol equivalent to a blood alcohol level mi a is one of the causes of mortality in (i.e., resorb) bone, and (2) osteoblasts, of 0.044 percent, about half the blood alcoholics with or without pre- e x i s t i n g which form new bone. alcohol level that many States define as he a r t disease. Such deaths often occur Cyclic bone remodeling continues legally intoxicated, also resulted in a during periods of abstinence (Clark th r oughout adulthood to regulate and 20 - p e r cent decline. Alcohol also may 1988), suggesting the development of maintain bone mass. Adult bone for- de p r ess osteoblast function by inhibit- arrhythmias during alcohol withdrawal. mation and resorption rates are tightly ing the cell’s response to -like coupled, with approximately 10 perce n t gr owth factors, chemical messengers Alcohol and of bone undergoing the process at any that help regulate bone rem o d e l i n g . gi v en time. Bet w een ages 20 and 40, a Studies of alcohol’s effects on osteo- The relationship between alcohol con- pe r s o n ’s bone density begins to decline, clast numbers have provided conflict- sumption and stroke is similar to that resulting in a cumulative decrease in ing results. Howeve r , alcohol increa s e s seen with CHD. Moderate alcohol skeletal mass of up to 40 percent by age le v els of a specific interleukin (IL-6), consumption appears to be associated 70. Women experience accelerated decline which may contribute to the devel o p - with lower incidence of ischemic strok e s , in bone density following menopause ment of osteoporosis by stimulating wh e r eas heavy drinking may increase the and are more susceptible than men to osteoclastic activity. risk of both ischemic and hemorrhagic os t e o p o ro s i s . st r okes (i.e., bleeding within the ). Alcohol disrupts bone rem o d e l i n g in animals and humans. Overall, studies in alcoholics suggest that alcoholic bone Alcohol and Bone disease invol v es considerable suppres - The lifetime risk for breast cancer among sion of bone formation with essentially U.S. women is estimated to be as high Epidemiologic studies have found a normal rates of resorption. The changes as one in eight. Results of approxi - significant association between alcohol in bone turnover induced by alcohol mately 50 epidemiologic studies and

30 Alcohol Research & Health Medical Consequences of Alcohol Abuse analyses conducted since the 1970s be r of studies have examined whether br east tissue—increase. In addition, point to an increase in breast cancer alcohol raises estrogen levels in pre- ROS can contribute to tumor prom o - risk associated with alcohol consump- menopausal and postmenopausal women. tion. Alcohol intake also decreases the tion. Controversy remains over the Although some studies rep o r t such an immune system’s ability to detect and in t e r p r etation of these studies, howeve r . effect, the evidence is not conclusive. For epidemiologists, the actual numeri- Alcohol may be capable of enhanc- de s t r oy cancer cells (Yirmiya and ■ cal association between alcohol and ing the prog r ession as well as the initia- Taylor 1993). br east cancer risk is considered rel a - tion of cancer. Inc r eased metastasis ti v ely modest. In addition, some stud- (p r oliferation beyond the site of origin) ies found no link between high alcohol of implanted breast cancer cells was References intake and breast cancer risk. ob s e r ved in rats given alcohol in a liq- uid diet. In addition, alcohol and its Selected references are presented. For a full list of highly rea c t i v e metabolite research cited, see the related article in the Te n t h Mechanisms of Alcohol-Related Special Report to the United States Congress on also have been linked to the body’s Breast Cancer . inability to repair damage to the cell’s Scientists have identified plausible bio- genetic material (i.e., DNA) induced Clark, J. Sudden death in the chronic alcoholic. logical mechanisms for alcohol’s actions. by cancer-causing agents. If unrep a i re d , Forensic Science International 36(1–2):105–111, 1988. Res e a r ch findings suggest a role for damage to critical regions of DNA in alcohol in breast cancer risk in both br east cells could lead to mutations and National Institute on Alcohol Abuse and Alcoholism. pr emenopausal and postmenopausal the subsequent initiation of cancer. Alcohol Alert No. 42: Alcohol and the Liver: Research Update. Bethesda, MD: The Institute, 1998. women. Cum u l a t i v e lifetime exposure When rodents are fed alcohol, their to estrogen is considered an importa n t le v els of circulating prolactin—a hor- Yirmiya, R., and Taylor, A.N., eds. Alcohol, Immunity contributor to breast cancer risk. A num- mone that can stimulate the growth of and Cancer. Boca Raton, FL: CRC Press, 1993.

New Materials To Address Underage Drinking

NIAAA has recently produced materials specifically aimed at addressing the problem of underage drinking. These materials may be ordered in quantities for school and other educational programs.

“Make a Difference: “Are You Working on Talk to Your Child Your GPA or You r About Alcohol” is a BAC?— Top Ten Myths research-based guide geared to About Alcohol.” This color- parents and guardians of young ful poster is geared to college-age people ages 10 to 14. Research students. It includes a tablet of shows that parents have an tear-off sheets featuring 10 of the enormous impact on their most common myths about drink- children’s behavior. This ing. Some of those myths include: booklet covers a number “I can sober up quickly if I have of topics, from strategies to,” “ doesn’t have as much to prevent underage drinking to recognizing alcohol as hard liquor,” “It’s okay for me the warning signs of a drinking problem. The to drink to keep up with my boyfriend,” and “I can booklet currently is available in English. A manage to drive well enough after a few drinks.” Spanish-language version soon will be available. Research-based facts are given to correct these common misconceptions.

To order, write to: National Institute on Alcohol Abuse and Alcoholism, Publications Distribution Center, P.O. Box 10686, Rockville, MD 20849–0686. Fax: (202) 842–0418. Full text of “Make a Difference: Talk to Your Child About Alcohol” is available on the World Wide Web at http://www.niaaa.nih.gov

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