Addiction B iolog y (1998) 3, 423 ± 433

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Gastritis in the alcoholic: relationship to gastric alcohol m etabolism and Helicobacter pylori CH AR LES S. LIEBER Alcohol Research and Treatm ent Center, Section of Liver Disease and N utr ition, B ronx Veterans AŒairs M edical C enter and the M ount Sinai School of M edicine, N ew York, USA

Abstract Chronic gastritis is comm on in the alcoholic. It is character ized by histologi cal in¯ am mation of the gastr ic mucosa and is associated with var iable sym ptom atolog y. Its etiology is still the subject of debate. R ecently, a new alcohol dehydrogena se isoenzym e, called sigm a ADH , absent from the liver but predominant in the upper GI tract, has been fully character ized, its gene cloned , and it appears to play a m ajor role in gastric etha nol metabolism . Indeed, it has now been esta blished, both in vivo in experim enta l animals and in vitro in culture d hum an gastric cells, that alcohol is m etabolized in the gastric m ucosa , resultin g in the production of acetaldehyde, a toxic m etabolite. In addition, Helicobacter pylori infection is com m on in the alcoholic, resultin g in the breakdown of urea to am monia, another tox ic product. A num ber of studies carried out over the last 40 years revealed that antibiotic treatm ent eradicates am monia production and results in histolog ical and sym ptom atic im provem ent in the m ajority of patients with alcoholic gastritis. Non-invasive tests for the detectio n of H. pylori are now available which will facilitate the large scale studies need ed to con® r m whether, in H. pylori -positive patients, antibiotics should becom e routine treatment for alcoholic gastr itis.

Introdu ction William Beaumont’s study of the ® stulous stomach of Alexis St M artin, and his observation that a large dose of alcohol taken acutely damages the gastric m ucosa, appears to be the earliest report of acute alcoholic gastritis. After alcohol ingestion, Beaumont noted mucosal erythema and super® cial ulcerations. This was con® rmed m ore recently in a prospective study in humans by Gottfried et al. 1 who documented that alcohol causes endoscopically visible antral erythema and friability and microscopic mucosal hem orrhage. Symptomatology and mechanisms for the patho-

genesis of these acute erosive /hem orrhagic gastric lesions, including a possible role for the alteration 2 in gastric mucus, are discussed elsewhere. The present brief review focuses on chronic gastritis which is common in the alcoholic.2 It is de® ned histologically as in¯ ammation of the mucosa, densely in® ltrated with mononuclear cells, accompanied by glandular atrophy. The pathogenesis is still debated. On one hand, since ethanol is metabolized in the stomach ( vide infra ), the resulting toxic acetaldehyde level could be incriminated in the pathogenesis of chronic gastric pathology, the same way as it was shown to

Correspondence to: Charles S. Lieber MD, Bronx VA Medical Center (151-2), 130 West Kingsbridge Road, Bronx, NY 10468, U SA. Tel: + 1 (718) 579 1646; fax: + 1 (718) 733 6257; e-mail: liebercs@ aol.com Received for publication 9th January 1998. Accepted 6th April 1998. 1355 ± 6215/98/040423 ± 11 $9.50 € Society for the Study of Addiction to Alcohol and Other Drugs Carfax Publishing Limited

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play a major role in chronic liver disease. On the other hand, the pathology and symptomatology of chronic gastritis in the alcoholic is similar to those of patients infected with H elicoba cter pylori (HP). C ompared to non-alcoholic subjects, the alcoholic patients were found to have a higher 3 incidence of chronic gastritis of the antrum, a lesion now known to be frequently associated with HP. Furthermore, HP infection is more common in heavy drinkers, as shown in a prospective study of 144 patients which revealed a statistically signi® cant relationship between high alcohol consumption and the presence of HP. 4 Therefore, the question of the respective role of alcohol and HP in the pathogenesis of gastritis in the alcoholic is an issue of direct therapeutic importance. However, as for the acute variety, much controversy has surrounded the issue of whether alcohol can cause chronic gastritis in man. Wolþ ,5 using a blind biopsy technique, detected no relationship between alcohol intake and histological evidence of atrophic gastritis, con® rming earlier observations by Palmer. 6 However, chronic gastritis in the alcoholic, like that associated with HP, 7 is usually of the ``B’ ’ type,8 namely it predominates in the antrum and, therefore, may have been m issed with the early rigid endoscopic instruments. Later studies with better instrumentation documented a connection between alcoholism and chronic gastritis.9 ± 1 1 12 Dinoso et al. found that, in the antrum, only 15.6% of alcoholics had a normal biopsy, with 65% having atrophic gastritis and only 50% having normal fundic histology compared to 85.7% of the controls. Thus, it is now germane to address the question of the respective role of ethanol and NH 3 .

Ethano l m etabolism an d its patho genic role in the stom ac h Alcohol was known to disappear from the stomach and this was considered to be part of its absorption from the gastrointestinal tract. It was quantitated postprandially by Cortot et al. 1 3 in seven healthy subjects. They found that of the ingested alcohol, 39.4 6 4.1% was absorbed through the stomach wall during the ® rst postprandial hour and 73.2 6 4.2% during the remaining time, whereas only 24 6 3% was absorbed during the same time in the duodenum. It was also known that when alcohol is taken orally, blood levels achieved are generally lower

than those obtained after administration of the same dose intravenously,1 4 ,1 5 so-called ® rst pass metabolism (FPM). Many drugs undergo FPM , which usually re¯ ects hepatic m etabolism. However, several observations had shown that the gastric mucosa also contains enzymes with alcohol dehydrogenase activity. The histochem ical observations 16 of Pestallozi et al. showed that the majority of super® cial mucosa cells in the stomach had signi® cant amounts of such activity. Since it was known that the bulk of ethanol absorbed m ust go through these cells when it disappears from the stomach, it made sense to postulate that some of this ethanol was metabolized in this passage through cells rich in ADH activity. However, when total ADH activity was m easured in the gastric mucosa under ``physiological conditions’’ , negligible activity was found in the stomach compared to the liver (Fig. 1). ``Physiological’’ was considered to be a concentration comm only seen in the blood and compatible with survival, such as levels at or below 50 m M . These are of course reasonable for the liver but not for the stomach, with the enzyme contained in super® cial cells immediately adjacent to the lumen where the concentration of ethanol is several magnitudes higher than in the blood. W hen the ethanol concentration in the test medium was increased, to mimic more realistically the situation in the stomach, the activity in the liver decreased (the well-known substrate inhibition) whereas that in the stomach increased, and eventually the two activities converged (Fig. 1). Two conclusions were reached from these observations, namely that alcohol metabolism in the stomach is not necessarily negligible, and that the enzyme(s) involved appear to be diþ erent from those in the livers because, unlike those in liver that show substrate inhibition (Fig. 1), the ones from the stomach did not. 18 Indeed, Herna ndez-M unÄ oz et al. then reported that the human gastric mucosa possesses several ADH isoenzymes, one of which is a class IV ADH (now called sigma-ADH) and is not present in the liver (Fig. 2). This enzyme has now been puri® ed,1 9 its full-length cDN A obtained and the complete amino acid sequence deduced.2 0 ,2 1 Using a nearly full-length cD NA, the gene (ADH 7 ) was obtained by Satre et al. ; 2 2 the full-length gene was cloned by Yokoyama et al.2 3 and localized to chromosome 4 (Fig. 3). The upstream structure of human AD H7 gene and the organ distribution of its expression was also de® ned.2 4

Alcohol dehydrogenase (m mol NADH/min/100 g body weight) (Mean ± SE)

Alcoholic gastritis

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4 Liver Stomach

3

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1

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Figure 1. Comparison between gastric and hepatic ADH activities ( per 100 g of body weight) at var ious ethanol 17 concentrations (data from Caballeria et al. ).

p

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16 15.3 15.2 15.1 14 13 12 11 centromere 11 12 13 14 21 22 ADH 23 ADH7 cluster 24 25 26 27 28 31.1 31.2 31.3 32 33 34 35 Chromosome 4

Figure 3. Mapping of AD H7 on Chromosome 4. AD H7 was found to be part of the cluster of other A DH isozymes 23 (data from Yokoyama et al. ). Figure 2. A DH isoenzymes in cytosol from gastric mucosa and liver obtained during surger y. Two bands of activity with slow cathodic mobility on starch gel electrophoresis were present in the gastric mucosa, but not in the liver. They correspond to what has been called l - or r -ADH (data 18 from Her na ndez-M unÄ oz et al. ).

Sigma ADH was found to have a high capacity for ethanol oxidation greater than that of the other

isozymes,1 9 yet there was still some resistance to the concept that the stomach may contribute signi® cantly to the overall ethanol metabolism of the body, despite the fact that this new view was supported by several lines of evidence. First the amount of ethanol that can be oxidized in the stomach was estimated experimentally: steady-

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state conditions were created in a group of rats by giving a loading dose of ethanol (2 g /kg body weight iv) in the fed state, followed by continuous 17 infusion, either intravenously or intragastrically. The rate of ethanol oxidation was calculated from the rate of infusion required to maintain steady blood levels of approximately 30 m M for at least 3 hours. Gastrointestinal ethanol concentrations and total contents also remained steady. The rate of ethanol oxidation was 19.3% faster during intragastric than during intravenous infusion ( p < 0.01). When measured at the prevailing luminal ethanol concentration, gastric ADH activity could account for m ost of this increased rate of oxidation when ethanol was given intragastrically. Gastric ADH was also found to be responsible for a large part of ethanol metabolism found in cultured rat2 5 and human 2 6 gastric cells. However, the relative contribution of gastric and hepatic ethanol metabolism in vivo , re¯ ected by the FPM 27± 30 of ethanol, is still the subject of debate. Speci® cally, the question was raised whether the diþ erence between blood alcohol concentration (BAC) after oral or intravenous administration 1 4 ,1 5 truly represents FPM or simply re¯ ects slower absorption of alcohol and, if there is FPM, is it mainly of gastric or hepatic origin? To study this, rats were given the same dose alcohol (1 g /kg) by either intragastric intubation or by intravenous, intraportal and intraduodenal infusions at a rate that mimicked the loss of alcohol from the stomach. Higher BAC levels after intravenous than intragastric alcohol were observed, indicating true FPM . In addition, higher levels after intraportal or intraduodenal infusions (in fact, comparable to those obtained with the intravenous route) demonstrated negligible FPM when the route of delivery bypassed the stomach, yet included the liver. Furtherm ore, rats that had developed portosystemic shunts after ligation of the portal vein exhibited blood alcohol curves and FPM equivalent to those of sham-operated controls, indicating that FPM is not dependent on ® rst-pass ¯ ow through the liver, but re¯ ects gastric metabolism. 3 1 The absence of signi® cant hepatic FPM was attributed to the saturation of hepatic alcohol dehydrogenase by recirculating alcohol, resulting in no appreciable increase in m etabolism secondary to newly absorbed alcohol. Finally, the in vivo gastric metabolism of alcohol in pylorus-ligated rats was demonstrated by signi® cantly lower BAC when alcohol was administered intragastrically than

when an amount identical to that lost from the ligated stomach was given intraportally. The above-mentioned studies indicated that the lower BAC with oral (as opposed to intravenous) alcohol do not appear to be simply a consequence of slow absorption, but result from FPM occurring predominantly in the stomach. This concept was supported indirectly by the observation that 32 commonly used drugs, such as aspirin, and some 1 8 ,3 3 H 2 -blockers, which decrease gastric ADH activity in vitro and /or accelerate gastric emptying, 3 4 also reduced ethanol metabolism by gastric cells 2 6 and produced increased blood alcohol levels in vivo , particularly at low alcohol doses, equivalent to social drinking. Although questioned at first, such increases in blood levels have now been con® rmed 3 5 ,3 6 for low ethanol doses. The BAC achieved by each single administration of such low doses is small, but social drinking is usually characterized by repetitive consumption of such small doses. Under those conditions, the eþ ect of the drug is cumulative,3 7 and the increase in BAC becomes suý cient to reach levels known 38± 40 to impair cognitive and ® ne motor function. Some ethnic diþ erences also support the concept of the role of gastric ADH in FPM of ethanol. Indeed, sigma-ADH is absent or markedly decreased in activity in a large percentage of Japanese subjects.4 1 Their FPM is correspondingly reduced,4 2 in keeping with a predominant role for sigma-ADH in human FPM . Thus, the FPM represents some kind of ``protective barrier’’ against the systemic eþ ects of ethanol, and its stimulation was invoked to explain some asso4 3 ,4 4 ciated attenuation of liver damage. Gender diþ erences have also been described: women have a greater vulnerability than men to the developm ent of organ damage after chronic alcoholic abuse, both in terms of liver disease4 5 ± 4 8 and brain damage.4 9 It is noteworthy that, in Caucasians, gastric ADH activity is lower in women than in men, 5 0 at least below the age of 50 years.5 1 There were associated higher BAC levels, an eþ ect more striking in alcoholic than in non-alcoholic wom en 5 0 because FPM is partly lost in the alcoholic,5 2 together with decreased gastric ADH activity. Furthermore, in women, the alcohol consumed is distributed in a 12% smaller water space5 0 because of a diþ erence in body composition (m ore fat and less water). The magnitude of FPM also depends on the concentration of the alcoholic beverages used. Indeed, gastric ADH isozymes require a relatively

Alcoholic gastritis

high ethanol concentration for optimal activity (vide supra ). Therefore, the concentration of alcoholic beverages aþ ects the amount metabolized, 5 3 with lesser FPM and higher BAC levels after beer than whisky5 4 for equivalent amounts of ethanol. Fasting also strikingly decreases FPM , 5 2 most probably because of accelerated gastric emptying, resulting in shortened exposure of ethanol to gastric ADH, and its more rapid intestinal absorption. Thus, to the extent that alcohol is being metabolized in the stomach, it does not penetrate the systemic circulation and, in that regard, gastric ethanol m etabolism may to a cer tain extent protect against the systemic eþ ects of alcohol. There is, however, a price to pay for this protection. When alcohol is being metabolized in the stomach, it is converted to acetaldehyde, a toxic metabolite, and some resulting gastric injury can be expected. It is possible, of course, that alternatively, or in addition, alcohol m ay favor gastric injury in some other ways. For instance, the alcohol (or acetaldehyde)-induced mucosal injury may, in turn, favor implantation of HP or its persistence in the stomach. As mentioned, some have observed an increased incidence of HP infection in the alcoholic,4 although there is no agreement on this point.5 5 Since both ethanol and the HPgenerated NH 3 activate cystein proteases,5 6 they also could potentiate each other’ s gastric toxicity. In any event, theoretically, reduction of acetaldehyde generation through inhibition of gastric ADH activity could be bene® cial. Provided that there is adequate simultaneous m oderation of alcohol consumption, this may become a new indication for the therapeutic use of H 2 blockers such as cim etidine shown to inhibit gastric, including sigma ADH, activity. 1 8 ,2 5 ,2 6,3 3 ,5 7 Additional bene® t could, of course, be derived from H 2 blockers’ primary eþ ect of gastric acid inhibition.

Role of Helicobacter pylori (H P ) and NH 3 HP may adversely aþ ect the stomach because of its high urease activity, which converts urea into NH 3 , the causticity of which was shown in cultured rat gastric cells.5 8 M oreover, in rats dietary ammonia loading for 2 weeks or longer resulted in a 1.5 ± 2-fold increase in the weigh and m ucosal thickness of the stomach and proximal duodenum, with evidence of m ild gastritis and hyperplasia of enterochromaý n-like cells.5 9 Thus, the pathogenic role of NH 3 in gastritis, long suspected, has now been m ore ® rm ly substantiated.

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The pathogenic role of NH 3 in gastritis had also been addressed directly in non-alcoholic HPpositive patients with chronic renal failure 6 0 in whom it was expected that high urea levels and, accordingly, elevated NH 3 concentrations might amplify the changes. Gastric urea and amm onia were measured and the severity of gastritis evaluated histologically by counting mononuclear and polymorphonuclear cells. High gastric ammonia and low urea in HP-positive patients, and the converse in HP-negative subjects, were observed. There was a signi® cant correlation ( p < 0.025) between gastric ammonia and interstitial polymorphonuclear leukocytes in® ltration, suggesting a causal link.6 0 Indeed, myeloperoxidase from neutrophils produces hypochlorous acid 6 1 which, in the presence of ammonia, yields m onochloramine, found to be very toxic in cultured rat gastric cells.5 8 Furthermore, suppression of HP was associated with a decrease in gastric juice NH 3 and an increase in urea, with a corresponding improvement in morphology.6 0 In 1957, measurement of gastric juice NH 3 (derived from urea) was considered a probable re¯ ection of bacterial infection when it was found, for the ® rst time, that the antibiotic oxytetracycline strikingly decreased gastric urease activity and NH 3 production in man, both in non-uremic (Fig. 4) and in urem ic (Fig. 5) subjects.6 2 ,6 3 The validity of gastric juice NH 3 measurement as a marker of HP infection 64 was reaý rm ed m ore recently. Since spirochetelike organisms had been described on the human gastric mucosa,6 5 ,6 6 it was postulated at that time 6 2 that the m ost probable explanation for the suppression of gastric NH 3 (and its replacem ent by unsplit urea) after oxytetracycline was the eradication of urease-producing microorganisms known to exist in the stomach. Indeed, urease activity had already been found in the stomach in 1924 by Luck & Seth,6 7 but they believed it to be intrinsic to the m ucosal cells. Accordingly, the alternate hypothesis was raised that, in the original study of Lieber & LefeÁ vre, 6 2 the tetracycline may not have been acting as an antibiotic but rather in some direct chemical way on a ``constitutive’ ’ urease present in the gastric cell. To address this objection, additional antibiotics were used.6 3 ,6 8 Although they diþ ered structurally, some of these were found to also decrease the urease activity. Thus, their eþ ect appeared to re¯ ect an antibacterial m echanism, indirectly con® rming the bacterial nature of gastric urease. The link between gastric infection and gastritis

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Charles S. Lieber 12

Basal secretion

Posthistamine secretion

Urea/ammonia levels (mMol/l (expressed as NH3))

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10 8 6 4 2

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Figure 4. M ean gastric am monia and urea concentrations in six non-uremic subjects. Concentrations in basal and posthistamine secretions are shown before and after 1 week of treatment with oxytetracycline (20 mg /kg /day p.o.) which 62 resulted in a signi® cant decrease in gastric am monia and corresponding increase in urea (data from Lieber & LefeÁ vre ).

Figure 5. Mean gastric NH 3 and urea concentrations in six urem ic patients. Concentrations in basal and posthistam ine secretions are shown before and after 1 week of treatment with oxytetracycline (20 mg /kg /day, p.o.) (data from Lieber & 63 LefeÁ vre ).

was further established by the rediscovery of ``unidenti® ed curved bacilli’’ associated with chronic gastritis 6 9 and their culture, and diþ erentiation from corresponding animal bacterial species. 7 0 The predominant organism involved

was identi® ed as Cam pylobacter (now reclassi® ed as H elicob acter pylor i ) and its contribution to gastritis7 1 and to the urease activity 7 2 was recognized. Thus, more than 40 years have now elapsed since the ® rst elimination of gastric urease-

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Alcoholic gastritis

Respective roles of alcoho l, NH 3 and their interactio ns in the pathogenesis of gastritis The question of the relative role of alcohol and NH 3 (hence HP) in the pathogenesis of the gastritis was addressed in a study conducted in 18 alcoholics with dyspepsia.7 3 HP was found in 14 individuals and was associated with chronic antral gastritis, whereas gastric biopsy specimens were normal in the 4 HP negative alcoholics. Assessments were repeated 3 ± 4 weeks after controlled abstinence during hospitalization. There was no change in histological ® ndings, indicating that alcohol itself was not the sole or major causative agent. In 10 HP positive alcoholics HP was eliminated with antibiotics, which resulted in almost complete normalization of histological ® ndings. Four control HP positive subjects who received only antacids showed no improvement. Dyspeptic symptoms were quanti® ed by a ``total dyspepsia score’’ based on severity of epigastric pain, nausea, vomiting, heartburn, halitosis, burping, postprandial bloating and ¯ atulence. They signi® cantly improved after antibiotic treatment and elimination of HP, whereas there was no change with antacids alone (Fig. 6). Because the clearance of HP correlated with resolution of the dyspeptic symptoms and histological improvement, it was concluded that HP played a predominant role in the pathogenesis and symptomatology of the chronic gastritis in these alcoholics,7 7 but there is still some question concerning the link between symptoms and histology (vide infra ).

Sym ptom atology of chro nic gastritis The link between histologic gastritis and symptoms has rem ained an elusive problem. Indeed, an age-related rise in HP gastritis occurs without an apparent increase in symptoms, and even asymptomatic subjects may have signs of gastritis in their biopsy specimens.7 8 However, some reported a

10

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Symptom score

producing bacteria by the use of antibiotics in man.6 2 In the interim , a causal link between HP and gastritis has been shown by the landmark 70± 74 experiments of M arshall et al. , as well as by the prospective studies of antibacterial treatment for chronic antral gastritis of Rauws et al.7 5 and others. 76 More recently, a larger and prospective study, as well as a direct comparison of the eþ ects of abstin77 ence from alcohol versus antibiotic therapy, also con® rmed the role of HP in chronic gastritis.

6

4

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0 Pre

Post Treatment

Figure 6. EŒect of treatm ent on symptom scores in Helicobacter pylori-positive alcoholics. Closed circles ( d ) indicate antacid treatment; open circles ( s ), antibacter ial treatm ent; p < 0.005 for scores before and after antibacter ial treatm ent; not signi® cant for scores before and after antacid treatm ent 77 (data from Uppal et al. )

signi® cant correlation between the in® ltration of antral mucosa with polymorphonuclear leukocytes and symptoms in patients with non-ulcer dyspepsia.7 9 Furthermore, it was already noted 40 years ago that, in patients with uremia, gastric amm onia suppression with antibiotics results in restoration of gastric acid secretion. 6 2 ,6 8 However, the question of the amelioration of gastritisassociated symptoms has been more elusive. Some investigators observed a signi® cant reduction in complaints,8 0 ± 8 2 whereas others found no symptomatic diþ erence between placebo and agents with antibacterial activity against HP.8 3 ± 8 5 These disparate results m ay have been due to the use of more eþ ective agents against HP in some studies than in others, or the contribution of aggravating factors, such as smoking.

D iag no stic and therap eutic im plications Thus far, diagnosis of HP infection has been based on histological detection of the organism or of its urease activity (e.g. Clo test) in biopsies of gastric mucosa,8 6 immunological detection of

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Charles S. Lieber 87

circulating antibodies to HP, as well as measurement of exhaled products of urea hydrolysis.8 8 ,8 9 It was also reported recently 6 4 that assessment of urease activity by the m easurement of NH 3 (relative to urea) present in the gastric juice provides an accurate, yet technically simpler diagnostic tool available in virtually all routine clinical laboratories. This procedure now facilitates a broader testing of individuals with dyspepsia who might be candidates for anti-HP treatment. The test has a high negative predictive value 6 4 and thereby may be particularly suited 9 0 for empirical anti-HP therapy of dyspepsia now being considered and /or recomm ended by Am erican, 9 1 ,9 2 as well as European 9 0 ,9 3 and Australian 9 0 authors. Speci® cally, in term s of alcoholic gastritis, the weight of the studies reviewed here should now be suý cient to consider, in addition to the control of drinking, the use of antibiotics in the same way that they are now accepted therapy for the 94 ulcer pathology caused or aggravated by HP. One may still, however, need large state-of-theart, randomized, placebo-controlled, doubleblind trials conducted in alcoholics to convince most m edical practitioners that alcoholic gastritis is indeed a legitimate indication for such treatment.

Acknow ledgem ents Original personal studies reviewed here were supported by the Departm ent of Veterans Aþ airs, the US Public Health Service and the Kingsbridge Research Foundation. Skilful typing of the manuscript by Ms Diana Moises and S. Dickerson is gratefully acknowledged.

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