Alcohol n GI

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mong the many organ systemsthat mediate alcohols effects onthe human body and its health,

the gastrointestinal (GI) tract plays aparticularly important part. Severalprocesses underlie this role. First, theGI tract is the site of alcohol absorptioninto the bloodstream and, to a lesser

extent, of alcohol breakdown and pro-duction. (For more information onalcohol absorption, metabolism, andproduction in the GI tract, see sidebar,pp. 8283.) Second, the direct contact ofalcoholic beverages with the mucosa1

that lines the upper GI tract can inducenumerous metabolic and functionalchanges. These alterations may lead tomarked mucosal damage, which canresult in a broad spectrum of acute andchronic diseases, such as acute gastro-

intestinal bleeding (from lesions in the

stomach or small intestine) and diar-

rhea. Third, functional changes and

mucosal damage in the gut disturb the

digestion of other nutrients as well as

their assimilation into the body, there-

by contributing to the malnutrition and

weight loss frequently observed in

alcoholics. Fourth, alcohol-induced

mucosal injuriesespecially in the

upper small intestineallow large

molecules, such as endotoxin and other

bacterial toxins, to pass more easily

into the blood or lymph. These toxic

substances can have deleterious effects

on the liver and other organs.

Over the past three decades, re-

searchers have made major progress

toward understanding alcohols many

acute and chronic effects on GI-tractfunction and structure.

This article reviews some of thesefindings, focusing primarily on insightsgained during the past 10 years. (Forextensive reviews of the developments

76 ALCOHOL HEALTH & RESEARCH WORLD

Alcohols Role in

Gastrointestinal Tract

Disorders

CHRISTIANE BODE, PH.D., AND J. CHRISTIAN BODE, M.D.

When alcohol is consumed, the alcoholic beverages first pass through the varioussegments of the gastrointestinal (GI) tract. Accordingly, alcohol may interfere withthe structure as well as the function of GI-tract segments. For example, alcohol canimpair the function of the muscles separating the esophagus from the stomach,thereby favoring the occurrence of heartburn. Alcohol-induced damage to themucosal lining of the esophagus also increases the risk of esophageal cancer. In thestomach, alcohol interferes with gastric acid secretion and with the activity of themuscles surrounding the stomach. Similarly, alcohol may impair the musclemovement in the small and large intestines, contributing to the diarrhea frequentlyobserved in alcoholics. Moreover, alcohol inhibits the absorption of nutrients in thesmall intestine and increases the transport of toxins across the intestinal walls,effects that may contribute to the development of alcohol-related damage to the liverand other organs. KEY WORDS: ethanol metabolism; AODE (alcohol and other drugeffects); mouth; esophagus; stomach; intestine; gastric mucosa; intestinal mucosa; gastric

lesion; gastric acid; gastrointestinal function; gastrointestinal absorption; muscle; neoplasticdisease; toxins; free radicals; etiology; literature review

CHRISTIANEBODE, PH.D., is professor

and chief of the Section of Physiologyof Nutrition (140), HohenheimUniversity, Stuttgart, Germany.

J. CHRISTIANBODE, M.D., is professorof medicine and chief of the Sectionof Gastroenterology, Hepatology and

Endocrinology in the Department ofInternal Medicine, Robert-Bosch-Krankenhaus, Stuttgart, Germany.

1For a definition of this and other technical terms used

in this article, see the central glossary, pp. 9396.

A


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in this field up to the early 1980s, seeBeazell and Ivy 1940; Bode 1980).

THE GI TRACTAN OVERVIEW

The GI tracts functions are to physi-

cally and chemically break downingested food, allow the absorption ofnutrients into the bloodstream, andexcrete the waste products generated.The GI tract can be viewed as onecontinuous tube extending from themouth to the anus (figure 1), which issubdivided into different segmentswith specific functions.

In the mouth, or oral cavity, the teethmechanically grind the food into smallpieces. Moreover, saliva excreted bythe salivary glands initiates the foodschemical degradation. From the oralcavity, the food passes through the throat(i.e., pharynx) into the esophagus. Thecoordinated contraction and relaxationof the muscles surrounding the esopha-gus propels the food into the stomach.

In the stomach, the chemical degra-dation of the food continues with thehelp of gastric acid and various diges-tive enzymes. Excessive gastric acidproduction can irritate the mucosa,causing gastric pain, and result in the

development of gastric ulcers. Twobands of muscle fibers (i.e., sphinc-ters) close off the stomach to the eso-phagus and the intestine. Weakness ofthe sphincter separating the stomachfrom the esophagus allows the stom-ach content to flow back into the eso-phagus. This process, which is calledgastroesophageal reflux, can lead toheartburn as well as inflammation (i.e.,reflux esophagitis) and even to thedevelopment of ulcers in the lowerpart of the esophagus.

From the stomach, the food entersthe small intestine, which is dividedinto three segments: the duodenum,the jejunum, and the ileum. Like theesophagus and stomach, the intestineis surrounded by layers of muscles,the rhythmic movements of whichhelp mix the food mass and push italong the GI tract. The intestinesinner mucosal surface is covered withsmall projections called villi, whichincrease the intestinal surface area

(figure 2). As the food mass movesthrough the small intestine, digestiveenzymes secreted by the intestinalcells complete the chemical degrad-ation of nutrients into simple mole-cules that can be absorbed through the

intestinal wall into the bloodstream.What finally remains in the intestineare primarily indigestible waste prod-ucts. These products progress into thelarge intestine, where the waste iscompacted and prepared for excretionthrough the anus. Like the small in-testine, the large intestine can bedivided into three segments: the ce-cum; the colon, which constitutesabout 80 percent of the large intes-tine; and the rectum. The followingsections review alcohols effect on thedifferent regions of the GI tract.

THE ORAL CAVITYAND THE ESOPHAGUS

The oral cavity, pharynx, esophagus,and stomach are exposed to alcoholimmediately after its ingestion. Thus,alcoholic beverages are almost undi-luted when they come in contact withthe mucosa of these structures. It istherefore not surprising that mucosal

injuries (i.e., lesions) occur quitefrequently in people who drink largeamounts of alcohol.2

Chronic alcohol abuse damages thesalivary glands and thus interfereswith saliva secretion. In alcoholics thisdamage commonly manifests itself asan enlargement (i.e., hypertrophy) ofthe parotid gland, although the mecha-nisms leading to this condition areunknown. Moreover, alcoholics maysuffer from inflammation of the tongue(i.e., glossitis) and the mouth (i.e.,

stomatitis). It is unclear, however,whether these changes result from

poor nutrition or reflect alcoholsdirect effect on the mucosa. Finally,chronic alcohol abuse increases theincidence of tooth decay, gum disease,and loss of teeth (Kranzler et al. 1990).

Alcohol consumption can affect theesophagus in several ways. For exam-

ple, alcohol distinctly impairs esophagealmotility, and even a single drinkingepisode (i.e., acute alcohol consump-tion) significantly weakens the loweresophageal sphincter. As a result,gastroesophageal reflux may occur,and the esophagus ability to clear therefluxed gastric acid may be reduced.Both of these factors promote theoccurrence of heartburn. Moreover,some alcoholics exhibit an abnormali-ty of esophageal motility known as a

VOL. 21, NO. 1, 1997 77

Gastrointestinal Tract Disorders

Oral cavity

Pharynx

Esophagus

Stomach

Duodenum

Jejunum

Cecum

Ileum

Largeintestine(colon)

Rectum

Teeth

Parotidgland

Salivaryglands

Tongue

Anal canal

Figure 1 Schematic representation of

the human gastrointestinal tract. The

small intestine comprises the duo-

denum, the ileum, and the jejunum.

2The alcohol amount necessary to cause mucosal

injury varies significantly among individual drinkers

and depends, for example, on whether alcohol

consumption occurs on an empty stomach or is

accompanied by a meal. Thus, no clear threshold

exists above which alcohol exerts its adverse effects.

However, the risk for adverse effects such as tissue

damage generally increases following the consump-

tion of more than 2 ounces of alcohol, which corre-

sponds to approximately four standard drinks (i.e.,

heavy or excessive drinking).


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nutcracker esophagus, which mim-

ics symptoms of coronary heart dis-

ease (Bode and Bode 1992).3

Chronic alcohol abuse leads to an

increased incidence not only of heart-

burn but also of esophageal mucosal

inflammation (i.e., esophagitis) and

other injuries that may induce mucosal

defects (i.e., esophagitis with or with-

out erosions). In addition, alcoholics

make up a significant proportion of

patients with Barretts esophagus. Thiscondition, which occurs in 10 to 20

percent of patients with symptomatic

gastroesophageal reflux disease

(Wienbeck and Berges 1985), is char-

acterized by changes in the cell layer

lining the esophagus (i.e., the epitheli-

um) that lead to abnormal acid produc-tion. A diagnosis of Barretts esopha-gus is an important indicator of anincreased risk of esophageal cancer,because in some patients the alteredepithelial cells become cancerous.

Another condition affecting alco-holics is Mallory-Weiss syndrome,which is characterized by massivebleeding caused by tears in the mucosaat the junction of the esophagus and thestomach. The syndrome accounts for 5

to 15 percent of all cases of bleeding inthe upper GI tract. In 20 to 50 percentof all patients, the disorder is caused byincreased gastric pressure resultingfrom repeated retching and vomitingfollowing excessive acute alcoholconsumption (Bode and Bode 1992).

THE STOMACH

Both acute and chronic alcohol con-sumption can interfere with stomach

functioning in several ways. For ex-ample, alcoholeven in relativelysmall dosescan alter gastric acidsecretion, induce acute gastric mucos-al injury, and interfere with gastricand intestinal motility.

Gastric Acid Secretion

Analyses in several animal speciesfound that acute alcohol administrationby mouth or by direct infusion into thestomach (i.e., intragastrically) or theblood (i.e., intravenously) can affectgastric acid secretion (Chari et al. 1993)The secretory response of the stomachvaries considerably, however, depend-ing on the species studied and the alco-hol concentrations used. In healthy,

nonalcoholic humans, intravenous alco-hol administration of 0.3 to 0.5 gramsper kilogram (g/kg) body weight orintragastric infusion of alcohol solutionswith concentrations of up to 5 percentstimulate gastric acid secretion, whereasintragastric infusion of higher concen-trations has either no effect or a mildlyinhibitory one (Chari et al. 1993). Accord-ingly, alcoholic beverages with a lowalcohol content (e.g., beer and wine)strongly increase gastric acid secretionand the release of gastrin, the gastric

hormone that induces acid secretion. Incontrast, beverages with a higher alco-hol content (e.g., whisky and cognac)stimulate neither gastric acid secretionnor gastrin release.

The mechanisms underlying theeffects of alcoholic beverages on gas-tric acid secretion have not yet beenidentified. Alcohol may interact direct-ly with the gastric mucosa (i.e., topicalstimulation); or, it may act through amore general mechanism affecting therelease of hormones and the regulation

of nerve functions involved in acidsecretion (Chari et al. 1993). More-over, researchers have shown that afterbeer consumption, gastric acid secre-tion also is stimulated by by-productsof the fermentation process other thanalcohol (Chari et al. 1993).

Chronic alcohol abuse also affectsgastric function. Thus, alcoholics havea significantly higher incidence ofshrinkage (i.e., atrophy) of the gastricmucosa and decreased gastric secretory


Intestinal muscles

Villi

Intestinal wall

Small Intestine

Submucosa

Intestinal muscles

Villi

Submucosa

Figure 2 Schematic illustration of the villi lining the small intestine. These villi serve

to increase the internal surface area of the intestine and thus enhance the

absorption of nutrients.

3The term nutcracker esophagus refers to the

painful, spasmodic contractions of the esophagus that

the patients who suffer the disorder describe as feeling

as though the esophagus were being squeezed by a

nutcracker.


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capacity than do healthy control sub-jects of comparable age and sex (Bodeand Bode 1992). The resulting decreasein acid production reduces the stomachsability to destroy the bacteria that enterwith food and thus favors the coloniza-

tion of the upper small intestine withpotentially harmful microorganisms.Abstinence, however, can at least partlyreverse these changes.

Acute Gastric Mucosal Injury

Researchers have known for morethan 100 years that alcohol abuse cancause mucosal inflammation (for areview, see Beazell and Ivy 1940). Inaddition, alcohol abuse is an importantcause of bleeding (i.e., hemorrhagic)

gastric lesions that can destroy parts ofthe mucosa. Although low or moder-ate alcohol doses do not cause suchdamage in healthy subjects, even asingle episode of heavy drinking caninduce mucosal inflammation andhemorrhagic lesions. Nonsteroidalanti-inflammatory drugs (e.g., aspirinand ibuprofen) may aggravate thedevelopment of alcohol-induced acutegastric lesions.

How alcohol damages the gastricmucosa has not yet been determined.

Studies in both animals and humanshave found that alcohol concentrationsof 10 percent and more disrupt thegastric mucosal barrier and increase themucosas permeability (Bode and Bode1992). The changes induced by short-term exposure to alcoholic beveragesare rapidly reversible. Prolonged alco-hol exposure, however, disturbs themicrocirculation and leads to progres-sive structural mucosal damage.

Several studies have suggested thatthe decreased formation of hormone-

like substances called prostaglandinsmight play a role in alcohol-inducedmucosal injury (Bode et al. 1996).Prostaglandins protect the gastricmucosa from damage by agents suchas aspirin that break the gastric mu-cosal barrier without inhibiting acidsecretion. Other studies have indicatedthat an alcohol-dependent increase inthe production of leukotrienescom-pounds produced by the immune sys-tem that cause allergic and

inflammatory reactionsalso mightcontribute to the development of alco-hol-induced mucosal injury (Bode andBode 1992).

Gastric and Intestinal Motility

Alcohol can interfere with the activityof the muscles surrounding the stom-ach and the small intestine and thusalter the transit time of food throughthese organs. In humans, alcoholseffect on gastric motility depends onthe alcohol concentration and accom-panying meals. In general, beverageswith high alcohol concentrations (i.e.,above 15 percent) appear to inhibitgastric motility and thus delay theemptying of the stomach. As a result

of the increased gastric transit time,bacterial degradation of the food maybegin; the resulting gases may lead tofeelings of fullness and abdominaldiscomfort.

In the small intestine, alcohol de-creases the muscle movements thathelp retain the food for further diges-tion (i.e., the impeding wave motility).In contrast, alcohol does not affect themovements that propel food throughthe intestine (i.e., the propulsive wavemotility) in either alcoholics or

healthy subjects. These effects maycontribute to the increased sensitivityto foods with a high sugar content(e.g., candy and sweetened juices),shortened transit time, and diarrheafrequently observed in alcoholics(Bode and Bode 1992).

THE SMALL INTESTINE

As described previously, the smallintestine is the organ in which mostnutrients are absorbed into the blood-

stream. Studies in humans and animalsas well as in tissue culture havedemonstrated that alcohol can inter-fere with the absorption of severalnutrients. Alcohol itself, however, alsois rapidly absorbed in the small intes-tine. In the human jejunum, for exam-ple, the alcohol concentration can dropfrom 10 percent to just 1.45 percentover a distance of only 30 centimeters(12 inches, about a quarter of the totallength of the jejunum) (Bode 1980).

Therefore, alcohols effects on nutri-ent absorption may vary throughoutthe small intestine, and tissue-cultureexperiments with constant alcoholconcentrations may not always reflectthe conditions in the body.

Studies in laboratory animals havedemonstrated that acute alcohol con-sumption can inhibit the absorption ofwater, sodium, glucose, and certainamino acids and fatty acids in the smallintestine (Bode 1980; Mezey 1985).Several studies in humans have ana-lyzed the effects of chronic alcoholconsumption with the following results:

Both in healthy people and in alco-holics, chronic alcohol consump-tion led to markedly reduced water

and sodium absorption in the je-junum and ileum (Bode and Bode1992; Pfeiffer et al. 1992).

Alcoholics exhibited a reducedabsorption of carbohydrates, pro-teins, and fats in the duodenum, butnot in the jejunum (Pfeiffer et al.1992) (see table).

Alcoholics without confoundingdisorders, such as cirrhosis orimpaired pancreatic function, ex-hibited malabsorption of fat and

protein (see table).

Alcoholics showed malabsorptionof xylose, a sugar frequently used tostudy the function of the digestivetract. The proportion of alcoholicswho experienced this malabsorptionranged from 18 to 76 percent invarious studies (see table). Thisvariation may reflect differences inthe nutritional status, the meandaily alcohol intake, or the presenceof alcohol-related liver disease

among the studies subjects. After chronic alcohol consump-

tion, the absorption of thiamine(vitamin B1), folic acid, and vita-min B12 was either unchanged ordecreased (Mezey 1985; Bode andBode 1992). Folic acid deficiency,which frequently occurs in alco-holics, can result in various disor-ders of the GI tract as well as inanemia. However, this deficiencyis more likely to result from a diet

VOL. 21, NO. 1, 1997 79



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containing insufficient folic acidthan from poor folic acid absorp-tion (Halstedt and Keen 1990).

In summary, alcohol inhibits ab-sorption of a variety of nutrients. Theimportance of these absorption disor-ders in the development of nutritionaldisturbances in alcoholics, however, isunclear. In alcoholics with limited

pancreatic function or advanced liverdisease, digestion of nutrients may bea more significant problem than im-paired absorption disorders.

Intestinal Enzymes

Alcohol can interfere with the activityof many enzymes that are essential forintestinal functioning. One of theseenzymes is lactase, which breaks downthe milk sugar lactose; lactase defi-ciency results in lactose intolerance.

Alcohol also interferes with some ofthe enzymes involved in transportingnutrients from the intestine into thebloodstream and inhibits importantenzymes that participate in the metab-olism of drugs and other foreign or-ganic substances in the gut (forreviews, see Mezey 1985; Bode 1980).

Intestinal Mucosal Injury

Excessive alcohol consumption fre-quently causes mucosal damage in the

upper region of the duodenum. Evenin healthy people, a single episode ofheavy drinking can result in duodenalerosions and bleeding. Animal studieshave indicated that several mecha-nisms contribute to the developmentof these mucosal injuries (Ray et al.1989) (for a review, see Bode andBode 1992). First, alcohol can directly

disturb the integrity of the mucosalepithelium. Second, alcohol inducesthe release of noxious signaling mole-cules, such as cytokines, histamine,and leukotrienes. These substancescan damage the small blood vessels,or capillaries, in the intestinal mucosaand induce blood clotting. Such clot-ting may lead to an impaired transportof fluids across the capillaries; fluidaccumulation under the tips of thevilli; and, eventually, destruction ofthe tips of the villi. The resulting

lesions allow large molecules, such asendotoxins and other bacterial toxins,to enter the bloodstream and the lymph.Third, as in the stomach, decreasedprostaglandin synthesis may contributeto changes in the capillaries and to thedevelopment of mucosal injury.

Intestinal Permeability

In animal studies, alcohol administra-tion increased the permeability of theintestinal mucosa, allowing large

molecules that normally cannot cross

the intestinal wall intact (e.g., hemo-

globin) to travel between the gut and

the bloodstream (Bode 1980).

Similarly, intestinal permeability was

enhanced in nonintoxicated alcoholics

(Bode and Bode 1992). The enhanced

permeability induced by acute and

chronic alcohol ingestion could allow

toxic compounds, such as endotoxin

and other bacterial toxins, to enter the

bloodstream and subsequently reach

the liver. The presence of endotoxin in

the blood has been documented in

patients with early stages of alcohol-

related liver damage and transiently,

after excessive alcohol consumption,

in people with no evidence of liver

disease (Fukui et al. 1991). Endotoxins

can induce the release of cytokines

(e.g., tumor necrosis factor) and inter-

leukins from certain white blood cells

and from Kupffer cells in the liver.

These cytokines, in turn, may play a

role in the development of alcohol-

related damage to the liver and other

organs (Khoruts et al. 1991; Schfer et

al. 1995) (figure 3). (For more infor-

mation on the association of endotoxin

and cytokines with liver damage, see

the article by Maher, pp. 512.)

Intestinal Bacterial Microflora

Certain bacteria that are a major

source of endotoxin may overgrow

the normal bacterial flora in the je-

junum of alcoholics (Bode and Bode

1992). Together with the altered per-

meability of the gut induced by alco-

hol, this process may allow an increased

escape of endotoxin from the intestine

into the blood vessels leading to theliver, thus increasing the livers expo-

sure to these toxins and, consequent-

ly, the risk of liver injury (figure 3).

The hypothesis that bacterial over-

growth may be responsible for the

development of alcohol-related organ

damage has been supported by the

observation that sterilization of the

intestine prevents alcohol-induced

liver injury in animal experiments

(Adachi et al. 1995).


Summary of Studies on Malabsorption of Carbohydrates, Fat, and Protein in

Alcoholics Without Cirrhosis or Obvious Pancreatic Insufficiency

A. Frequency of Abnormal Absorption Among Alcoholics

% Subjects

Nutrient Studied Number of Studies With Abnormal Absorption

D-Xylose 5 1876

Fata 2 3556

Proteinb 1 52

B. Mean Decrease in Absorption Compared With Nonalcoholic Controlsc

Nutrient Studied % Decrease

Carbohydrates 45

Lipids 40

Protein 81

aFat absorption was determined by measuring fat excretion in the feces.

bProtein absorption was determined by measuring nitrogen excretion in the feces.cThe study measured the absorption of a nutrient solution in the duodenum.

SOURCES: A: Bode and Bode 1992; B: Pfeiffer et al. 1992.


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The Large Intestine

Until recently, alcohols effects onthe large intestine had received onlyminor attention. Studies in dogsfound that acute alcohol administra-

tion depressed the colons impedingmotility but enhanced its propulsive

motility (Mezey 1985). In healthyhumans, alcohol administration alsosignificantly reduced the frequencyand strength (i.e., amplitude) of themuscle contractions in a segment ofthe rectum (Mezey 1985). Theseeffects could reduce the transit timeand thus the compactionof theintestinal contents and thereby con-tribute to the diarrhea frequentlyobserved in alcoholics.

MEDICAL CONSEQUENCES

Alcohol-induced digestive disorders andmucosal damage in the GI tract cancause a variety of medical problems.These include a loss of appetite and amultitude of abdominal complaints, suchas nausea, vomiting, feelings of fullness,flatulence, and abdominal pain. Diseasesof the liver and pancreas may contributeto and aggravate these complaints. Thus,about 50 percent of alcoholics with an

initial stage of liver damage (i.e., fattyliver) and 30 to 80 percent of patientswith an advanced stage of alcohol-in-duced liver injury (i.e., alcoholic hepati-tis) report some symptoms of abdominaldiscomfort (Bode and Bode 1992). Theseabdominal complaints can lead to re-duced food intake, thereby causing theweight loss and malnutrition commonlyobserved in alcoholics.

In addition to causing abdominalcomplaints, alcohol plays a role in thedevelopment of cancers of the GI tract.It is likely, however, that alcohol doesnot cause GI-tract cancers by itself butacts in concert with other cancer-induc-ing agents (i.e., as a cocarcinogen) (forreviews, see Seitz and Simanowski1988; Garro and Lieber 1990). Alcoholabuse, like smoking, is associated withthe development of cancers of the tongue,larynx (i.e., the organ of voice), andpharynx; both alcohol consumption andsmoking independently increase therisk for these tumors (Bode 1980).

Epidemiological studies also stronglyindicate that chronic alcohol consump-tion, especially of distilled spirits,

markedly contributes to the develop-ment of esophageal cancer (Bode 1980;Wienbeck and Berges 1985). Thus,after adjusting for smoking habits,heavy beer drinkers have a 10 times

greater risk and heavy whisky drinkersa 25 times greater risk of developingesophageal cancer, compared withpeople who consume less than 30 g ofalcohol (i.e., about 2 standard drinks)daily. The differences between beer andwhisky drinkers remain even if they

consume the same amount of purealcohol. In drinkers who also smoke 20

cigarettes or more daily, the risk ofesophageal cancer increases about 45-fold (Seitz and Simanowski 1988).

Heavy alcohol consumption also isassociated with the development oftumors in the colon and rectum. How-ever, the relative risk of cancer is higherfor rectal cancer than for colon cancer.Moreover, the increased risk of rectal

cancer appears to result mainly from

heavy beer consumption, whereasdistilled spirits appear to have no effect.

SUMMARY

Alcohol consumption can interfere withthe function of all parts of the gastroin-testinal tract. Acute alcohol ingestioninduces changes in the motility of theesophagus and stomach that favor gas-troesophageal reflux and, probably, thedevelopment of reflux esophagitis.Alcohol abuse may lead to damage ofthe gastric mucosa, including hemor-rhagic lesions. Beverages with a low

alcohol content stimulate gastric acidsecretion, whereas beverages with ahigh alcohol content do not.

In the small intestine, alcohol in-hibits the absorption of numerousnutrients. The importance of theseabsorption disorders for the develop-ment of nutritional disturbances inalcoholics, however, is unclear. Inalcoholics with other digestive disor-ders (e.g., advanced liver disease orimpaired pancreatic function), impaired

VOL. 21, NO. 1, 1997 81


Disturbed absorption

Damage to the blood vesselsand disturbed microcirculation

Liver cell injury andother organ injury

Increased uptake of endotoxinsand other toxins into thebloodstream and lymph

Increased release of cytokinesand other mediators from certainwhite blood cells and Kupffer cells

Small intestine

Alcohol

Disturbedmotility

Bacterial overgrowth

Decreasedprostaglandin synthesis

Increased formation ofendotoxins and other toxins

Mucosal lesions andincreased permeability

Figure 3 Schematic presentation of the possible causes and consequences of

mucosal injury, increased permeability of the intestinal mucosa to macro-

molecules, and bacterial overgrowth in the small intestine of chronic

alcohol abusers. Thickness of arrows indicates strength of association

between phenomena. (For definitions, see glossary, pp. 9396.)


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digestion likely is more significant.Acute alcohol consumption also dam-ages the mucosa in the upper region ofthe small intestine and may even leadto the destruction of the tips of thevilli. The findings of human and ani-

mal studies suggest that these mucosaldefects favor the following sequenceof events: Alcohol-induced mucosaldamage in the small intestine increas-es the mucosas permeability, facili-tating the transport of large molecules,such as bacterial endotoxin and/orother toxins, into the blood or lymph.This results in the release of potential-ly toxic cytokines by certain white

blood cells and Kupffer cells. These

cytokines, in turn, exert multiple inju-

rious effects on membranes and the

microcirculation. The result is possi-

ble cell damage and even cell death in

the liver and other organs.

Motility disorders, maldigestion,

and malabsorption in alcoholics can

result in digestive problems, such as

anorexia, nausea, and abdominal pain.

Alcohol abuse also promotes the de-

velopment of cancers of the tongue,

larynx, pharynx, and esophagus. Finally,

the results of recent epidemiological

studies indicate an association between


The excessive consumption ofalcoholic beverages interferes withthe normal function and structureof the gastrointestinal (GI) tract.The relationship between alcoholand the GI tract is a two-way street,however, and the GI tract plays arole in the absorption, metabolism,and production of alcohol.

Absorption

Throughout the GI tract, alcoholabsorption into the bloodstreamoccurs through a process calledsimple diffusion. The rate at whichthis process occurs depends onseveral factors, primarily the dif-ference between the alcohol con-centrations in the GI organs and inthe adjacent small blood vessels,the regional blood flow, and the

permeability of the GI tract lining(i.e., the mucosa) in question. Forexample, the higher the concentra-tion of the ingested alcohol, themore alcohol the mucosa absorbs.In contrast, the presence of food inthe stomach decreases the rate ofalcohol absorption. Other factorsthat may affect alcohol absorptioninclude the type of alcoholic bever-age, the drinkers gender and body

NAD+

Alcohol Acetaldehyde Acetate

ADH ALDH

NAD+

The pathway of alcohol metabolism. Once in the liver, alcohol is converted into

acetaldehyde, and the acetaldehyde is converted into acetate. The enzyme alco-

hol dehydrogenase (ADH) assists the chemical reaction in (i.e., catalyzes) thefirst half of alcohol metabolism, and the enzyme aldehyde dehydrogenase (ALDH)

catalyzes the second half. NAD+ is a coenzyme that plays an accessory role in

enzyme catalysis.

ALCOHOL ABSORPTION, METABOLISM, ANDPRODUCTION IN THE GASTROINTESTINAL TRACT

temperature, the presence of certainmedications in the body, and thetypes of spices in the food (Bode1980). For example, alcohol absorp-tion occurs more slowly after theingestion of beer than after the inges-tion of an equal amount of alcohol inthe form of whisky or brandy. Mostof these factors probably inhibit orenhance alcohol absorption by affect-ing the movement of the stomachmuscles (i.e., gastric motility) andsmall intestinal blood flow.

Metabolism

More than two decades ago,research-ers found that the initialbreakdown of alcohol (i.e., first-pass

metabolism) occurs not only in theliver, as with most other nutrients,but also in the stomach and the smallintestine (Mezey 1985). The enzymealcohol dehydrogenase (ADH),which mediates the first step of alco-hol degradation (see figure), is pre-sent in the mucosa of the stomach

and the small intestine. In fact, sever-al ADH variants (i.e., isoenzymes)with different kinetic properties existin the mucosa of the GI tract; theseisoenzymes permit alcohol metab-olism over a wide range of concen-trations. The ADH isoenzyme patternin the GI tract differs from that foundin the liver.

Some researchers have postulatedthat first-pass metabolism in humans

alcohol consumption and the develop-ment of colorectal cancer. s

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VOL 21 NO 1 1997 83


occurs primarily in the stomach

(Gentry et al. 1994) and correlatessignificantly with gastric ADH activi-ty. However, other investigators havequestioned the stomachs role in first-pass alcohol metabolism (Levitt1994). The proportion of alcoholeliminated by gastric first-passmetabolism also remains controver-sial (Sato and Kitamura 1996); com-pared with hepatic alcohol degradation,gastric first-pass metabolism seems tobe quantitatively important only atlow alcohol concentrations. In wom-

en, first-pass metabolism is less effi-cient than in men. Consequently,women achieve higher blood alcoholconcentrations than men with thesame low gastric alcohol concentra-tion because more alcohol passesfrom a womans stomach into thesmall intestine, where it is absorbedinto the bloodstream. Furthermore,gastric first-pass metabolism decreas-es with long-term alcohol consump-tion, partly because of diminishedADH activity (Gentry et al. 1994).

A recent study suggests that alcoholalso can be metabolized by bacteriaresiding in the large intestine (Sala-spuro 1996). In this pathway, alcoholis transported to the colon via thebloodstream and converted to acetalde-hyde by bacterial ADH (see figure).The acetaldehyde subsequently can bemetabolized further by the enzymealdehyde dehydrogenase (ALDH),which is localized in the colonic mu-

cosa or the colonic bacteria.

Alternatively, the acetaldehyde can beabsorbed into the bloodstream andtransported to the liver for furtherdegradation. Because ALDH activityin the colonic mucosa is low,acetaldehyde accumulates in the colonand may even exceed the concentra-tion found in the liver (Salaspuro1996). These high acetaldehyde levelsin the colon may contribute to thedevelopment of alcohol-induced diar-rhea andafter absorption into thebloodliver injury.

Production

In many animal species, includinghumans, alcohol is not only degradedbut also produced in the GI tract. Thisalcohol production is a by-product ofthe bacterial breakdown of ingestedcarbohydrates. Alcohol also is formedin the human stomach, and in patientswith disturbed gastric emptying, theconcentrations can be as high as 0.35percent (i.e., about four times as highas the blood alcohol levels for intoxi-cation) (Bode and Bode 1992). Twofactors favor gastric alcohol productionin these patients. First, they produceless gastric acid and thus allow theproliferation of bacteria in the stom-ach. Second, the patients retain theirfood in the stomach for an extendedperiod of time. Both factors lead to anincrease in the bacterial degradation of

nutrients and thus an increase in

alcohol production.

Christiane Bode and

J. Christian Bode

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SATO, N., AND KITAMURA, T. First-pass

metabolism of ethanol: An overview.

Gastroenterology 111:11431150, 1996.

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