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


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@ 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


Charles S. Lieber 2

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


4 Liver Stomach








300 400 Ethanol (mM)




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. ).




q 2


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-


Charles S. Lieber

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.


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


Charles S. Lieber 12

Basal secretion

Posthistamine secretion

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

Ammonia Urea

10 8 6 4 2






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-


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



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.




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


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.

References 1. Gottfried EB, Korsten M A, Lieber CS. Alcoholinduced gastric and duodenal lesions in man. Am J Gastroenterol 1978;70:58 7 ± 92. 2. Lieber CS. Medical and nutritional complications of alcoholism : mechanism s and m anagement. New York: Plenum Press; 1992, p. 579. 3. Parl FF, Lev R, Thomas E, Pitchumoni CS. Histologic and m orphometric study of chronic gastritis in alcohol patients. Hum Pathol 1979;10:4 5 ± 56. 4. Pateron D, Fabre M, Ink O et al. In¯ uence de l’ alcool et de la cirrhose sur la preÂsense de Helicobacter pylori dans la m uqueuse gastrique. G astroenterol Clin Biol 1990;14:5 55 ± 68. 5. Wolþ G. Does alcohol cause chronic gastritis? Scand J G astroenterol 1970;4:28 9 ± 91. 6. Palmer ED. Gastritis: a reevaluation. M edicine 1954;33:19 9 ± 290.

7. H azell SL, H ennessy W B, Borody TJ, et al. Cam pylobacter pyloridis gastritis II: distribution of bacteria and associated in¯ amm ation in the gastroduodenal environm ent. Am J Gastroenterol 1987;82:2 97 ± 301. 8. Strickland RG , Mackay IR. A reappraisal of the nature and signi® cance of chronic atrophic gastritis. Dig Dis 1973;18:42 6 ± 37. 9. Joske R A, Fineki ES, Wood LJ. Gastric biopsy: a study of 1000 consecutive biopsies. Q J M ed 1955; 48:269 ± 94. 10. Rober ts DM. Chronic gastritis, alcohol and nonulcer dyspepsia. G ut 1972;13:76 8 ± 74. 11. Pitchumoni G S, G lass G BJ. Alcohol injury to the gastrointestinal mucosa. In: G lass G BJ, editor. Progress in gastroenterology. New York: G rune & Stratton; 1977, pp. 717 ± 58. 12. Dinoso VP, Chey W Y, Braverman SP. Gastric secretion and gastric m ucosal m orphology in chronic alcoholics. Arch Int M ed 1972;130: 715 ± 20. 13. Corto A, Jobin G , Fucrot F, Aym es C, G iraudeaux V, Modigliani R. G astric emptying and gastrointestinal absorption of alcohol ingested with a m eal. Dig Dis Sci 1986;31:3 43 ± 8. 14. Julkunen RJK , DiPadova C, Lieber CS. First pass m etabolism of ethanol a gastrointestinal barrier against the systemic toxicity of ethanol. Life Sci 1985;37:5 67 ± 73. 15. Julkunen RJK , Tannenbaum L , Baraona E, Lieber CS. First pass m etabolism of ethanol: an important determ inant of blood levels after alcohol consumption. Alcohol 1985;2:437 ± 41. 16. Pestallozi DM , Buhler R, von Wartburg JP, Hess M . Immunohistochemical localization of alcohol dehydrogenase in the hum an gastrointestinal tract. G astroenterology 1983;85:10 11 ± 16. 17. Caballeria J, Baraona E, Lieber CS. The contribution of the stomach to ethanol oxidation in the rat. Life Sci 1987;41:10 21 ± 7. 18. H erna ndez-MunÄ oz R, Caballeria J, Baraona E, U ppal R, G reenstein R, Lieber CS. Hum an gastric alcohol dehydrogenase: its inhibition by H 2-receptor antagonists, and its eþ ect on the bioavailability of ethanol. Alcohol Clin Exp Res 1990;14:94 6 ± 50. 19. Stone CL, Thom as HR, Bosron W F, Li T-K . Puri® cation and partial amino acid sequence of a high activity hum an stomach alcohol dehydrogenase. Alcohol Clin Exp Res 1993;17:91 1 ± 18. 20. Yokoyama H, Baraona E, Lieber CS. M olecular cloning of hum an class IV alcohol dehydrogenase. Biochem Biophys Res Comm 1994;203:2 19 ± 24. 21. FarreÁ s J, Moreno A, Crosas B, et al. Alcohol dehydrogenase of class IV ( d AD H) from hum an stomach; cDNA sequence and structure /function relationships. Eur J Biochem 1994;224: 549 ± 57. 22. Satre MA, Zgombic-Knight M , Duester G. The complete structure of hum an class IV alcohol dehydrogenase (retinol dehydrogenase) determined from AD H7 gene. J Biol Chem 1994;269: 15606 ± 12. 23. Yokoyama H, Baraona E, Lieber CS. M olecular cloning and chromosomal localization of AD H 7 gene encoding hum an class IV AD H. Genomics 1996;31:2 43 ± 5.

Alcoholic gastritis 24. Yokoyama H, Baraona E, Lieber CS. U pstream structure of hum an A DH7 gene and the organ distribution of its expression. Biochem Biophys Res Comm 1995;216: 216 ± 22. 25. Mirm iran-Yazdy SA, H aber PS, Korsten MA et al. Metabolism of ethanol in rat gastric cells and its inhibition by cimetidine. G astroenterology 1995; 108:737 ± 42. 26. Haber PS, Gentry T, Mak KM , M irmiran-Yazdy AA, G reenstein RJ, Lieber CS. M etabolism of alcohol by human gastric cells: relation to ® rst pass metabolism. G astroenterology 1996;111:8 63 ± 70. 27. Smith T, DeMaster EG, Furne JK, spring® eld J, Levitt MD. First-pass gastric mucosal m etabolism of ethanol is negligible in the rat. J Clin Invest 1992;89:18 01 ± 6. 28. Levitte MD, Levitt DG. The critical role of the rate of ethanol absorption in the interpretation of studies purporting to demonstrate gastric m etabolism of ethanol. J Pharmacol Exp Ther 1994;269:2 97 ± 304. 29. Lieber CS, G entry RT, Baraona E. First pass metabolism of ethanol. In: Saunders JB, W hit® eld JB, editors. The biology of alcohol problems. UK : Elsevier Science Publishers; 1996, pp. 315 ± 26. 30. Sato N, Kitamura T. First-pass m etabolism of ethanol: an overview. G astroenterology 1996;111: 1143 ± 4. 31. Lim Jr RT, G entry RT, Ito D, Yokoyama H , Baraona E, Lieber CS. First pass m etabolism of ethanol in rats is predominantly gastric. Alcohol Clin Exp Res 1993;17:13 37 ± 44. 32. Roine RP, Gentry RT, Herna ndez-M unÄ oz R, Baraona E, Lieber CS. Aspirin increases blood alcohol concentrations in human after ingestion of ethanol. JAM A 1990;264: 2406 ± 8. 33. Caballeria J, Baraona E, Rodamilans M, Lieber CS. Eþ ects of cimetidine on gastric alcohol dehydrogenase activity and blood ethanol levels. G astroenterology 1989;96:3 88 ± 92. 34. Amir I, Anwar N, Baraona E, Lieber CS. Ranitidine increases the bioavailability of imbibed alcohol by accelerating gastric emptying. Life Sci 1996;58: 511 ± 18. 35. Palmer R H, Frank WO, Nambi P, Wetherington JD , Fox MJ. Eþ ects of various concomitant m edications on gastric alcohol dehydrogenase and ® rstpass m etabolism of ethanol. Am J G astroenterol 1991;86:17 49 ± 55. 36. Fraser AG , Hudson M, Sawyer AM , Rosalki SM , Pounder R E. Short report: the eþ ect of ranitidine on post-prandial absorption of a lowe dose of alcohol. Alim ent Pharmacol Ther 1992;6:267 ± 71. 37. G upta AM , Baraona E, Lieber CS. Signi® cant increase of blood alcohol by cimetidine after repetitive drinking of sm all alcohol doses. Alcohol Clin Exp Res 1995;19:10 83 ± 7. 38. Klein KE, Breuker K, BruÈ ner H, Wegm ann HM . Blutalkohol und Fluguntuchtigkeit. Versuch einer Erarbeitung von Richtwerten fuÈ r die allgemeine Luftfahrt. Int Z Angew Physiol 1067;24:25 4 ± 7. 39. Moskowitz H, Burns MM , W illiams AF. Skill performance at low blood alcohol levels. J Stud Alcohol 1985;46:48 2 ± 5. 40. Modell JG, M ountz JM . Drinking and ¯ yingÐ the


















problem of alcohol use in pilots. N Engl J Med 1990;323: 455 ± 61. Baraona E, Yokoyama A, Ishii H et al. Lack of alcohol dehydrogenase isoenzym e activities in the stomach of Japanese subjects. Life Sci 1991;49: 1929 ± 34. Dohmen K, Baraona E, Ishibadsshi H et al. Ethnic diþ erences in gastric sigm a alcohol dehydrogenase activity and ethanol ® rst pass metabolism. Alcohol Clin Exp Res 1996;20:1 569 ± 76. Battiston L, Moretti M, Tulissi P et al. Hepatic glutathione determination after ethanol administration in rat: evidence of the ® rst-pass m etabolism of ethanol. Life Sci 1994;56:24 1 ± 8. Iimuro Y, Bradford BU, Forman DT, Thurm an RG. G lycine prevents alcohol-induced liver injury by decreasing alcohol in the rat stomach. G astroenterology 1996;110:1 536 ± 42. M organ MY, Sherlock S. Sex-related diþ erences among 100 patients with alcoholic liver disease. Br M ed J 1977;1:939 ± 41. Pequignot G , Tuyns AJ, Ber ta JL. Ascitic cirrhosis in relation to alcohol consumption. Int J Epidemiol (Lond) 1978;7:113 ± 20. Parrish KM, Dufour M C, Stinson FS, Harford TC. Average daily alcohol consumption during adult life among decedents w ith and without cirrhosis: the 1986 National M ortality Followback Survey. J Stud Alcohol 1993;54:45 0 ± 6. Becker U, Deis A, Sorenson TIA et al. Prediction of risk of liver disease by alcohol intake, sex, and age: a prospective population study. H epatology 1996;23:1 025 ± 9. M ann K, Batra A, GuÈ nthner A, Schroth G. Do women develop alcoholic brain damage more readily than m en? Alcohol Clin Exp Res 1992;16: 1052 ± 6. Frezza M, Di Padova C, Pozzato G , Terpin M, Baraona E, Lieber CS. High blood alcohol levels in women. The role of decreased gastric alcohol dehydrogenase activity and ® rst-pass m etabolism. N Engl J M ed 1990;322: 95 ± 9. Seitz H K, Egerer G , Sim anowski UA et al. Hum an gastric alcohol dehydrogenase activity: eþ ect of age, gender and alcoholism . Gut 1993;34:14 33 ± 7. Di Padova C, Worner T M, Julkunen RJK , Lieber CS. Eþ ects of fasting and chronic alcohol consumption on the ® rst pass m etabolism of ethanol. G astroenterology 1987;92:11 69 ± 73. Roine RP, G entry RT, Lim Jr RT, Baraona E, Lieber CS. Eþ ect of concentration of ingested ethanol on blood alcohol levels. Alcohol Clin Exp Res 1991;15:7 34 ± 8. Roine RP, Gentry RT, Lim Jr RT, H eikkonen E, Salaspuro M, Lieber CS. Comparison of blood alcohol concentrations after beer and w hiskey. Alcohol Clin Exp Res 1993;17:70 9 ± 11. Laine L. Helicobacter pylori, gastric ulcer, and agents noxious to the gastric m ucosa. G astroenterol Clin N Am 1993;22:1 17 ± 25. Nagy L, Kusststsche S, Hauschka PV, Szabo S. Role of cysteine proteases and protease inhibitors in gastric m ucosal damage induced by ethanol or amm onia in the rat. J Clin Invest 1996;98:10 47 ± 54.


Charles S. Lieber

57. Stone CL, H urley TD, Peggs CF et al. Cimetidine inhibition of hum an gastric and liver alcohol dehydrogenase isoenzymes: identi® cation of inhibitor complexes by kinetics and m olecular m odeling. Biochem istry 1995;34:40 08 ± 14. 58. Dekigai H, M urakami M , Kita T. M echanism of Helicobacter pylori-associated gastric mucosal injury. Dig Dis Sci 1995;40:13 32 ± 9. 59. Lichtenberger LM, Dial EJ, Rom ero JJ, Lechago J, Jarboe L A, Wolfe M M. Role of luminal amm onia in the development of gastropathy and hypergastrinem ia in the rat. Gastroenterology 1995;108: 320 ± 9. 60. Triebling AT, Korsten M A, Dlugosz JW, Paronetto F, Lieber CS. Severity of Helicobacter-induced gastric injury correlates with gastric juice ammonia. Dig Dis Sci 1991;36:10 89 ± 96. 61. Murakami M , Asagoe K, Dekigai H, Kusaka S, Saita H , Kita T. Products of neutrophil m etabolism increase ammonia-induced gastric m ucosal damage. Dig Dis Sci 1995;40:26 8 ± 73. 62. Lieber CS, LefeÁvre A. Eþ ect of oxytetracycline on acidity, ammonia and urea in gastric juice in norm al and uremic subjects. CR Soc Biol (Paris) 1957; 151:1038 ± 42. 63. Lieber CS, LefeÁvre A. Am monia as a source of gastric hypoacidity in patients with uremia. J Clin Invest 1959;38:12 71 ± 7. 64. Mokuolu AO, Sigal SH, Lieber CS. Gastric juice urease activity as a diagnostic test for H elicobacter pylori infection. Am J G astroenterol 1997;92: 644 ± 8. 65. Doenges JL. Spirochetes in the gastric glands of Macacus rhesus and of man without related disease. Arch Pathol Lab M ed 1939;27:4 69 ± 77. 66. Freedburg AS, Barron LE. The presence of spirochetes in hum an gastric m ucosa. Am J Dig Dis 1940;7:443 ± 5. 67. Luck JM , Seth TN. Gastric urease. Biochem J 1924;18:12 27 ± 31. 68. Meyers S, Lieber CS. Reduction of gastric ammonia by ampicillin in normal and azotemic subjects. Gastroenterology 1976;70:2 44 ± 7. 69. Warren JR. U nidenti® ed curved bacilli on gastric epithelium in active chronic gastritis. Lancet 1983; 1:1272. 70. Marshall M J. Unidenti® ed curved bacilli on gastric epithelium in active chronic gastritis. Lancet 1983; 1:1273 ± 5. 71. Marshall BJ, McGechie DB, Rogers PA, Glancy RJ. Pyloric Cam pylobacter infection and gastroduodenal disease. Med J Aust 1985;142:4 39 ± 44. 72. Marshall BJ, Langton SR. Urea hydrolysis in patients with Cambylobacter pyloridis infection. Lancet 1986;1:965 ± 6. 73. Marshall BJ, Arm strong JA, McGechie DB, G lancy RJ. Attem pts to ful® l Koch’ s postulates for pyloric Cam pylobacter. Med J Aust 1985;142:4 36 ± 9. 74. Morris A, Nicholson G. Ingestion of Cam pylobacter pyloridis causes gastritis and raising fasting pH . Am J Gastroenterol 1987;82:19 2 ± 9. 75. Rauws EAJ, Langenberg W, Houthoþ HJ, Zanen HC, Tytgat G NJ. Cam pylobacter pyloridis-associated chronic active antral gastritis: a prospective study
















of its prevalence and the eþ ects of antibacterial and antiulcer treatment. G astroenterology 1988; 94:33 ± 40. Kudo M, Asaka M , Kato M et al. Role of Helicobacter pylori in chronic gastritis: a prospective study. J Clin Gastroenterol 1995;2:S17 4 ± 8. U ppal R, Lateef SK , Korsten M A, Paronetto F, Lieber CS. Chronic alcoholic gastritis: roles of alcohol and Helicobacter pylori. Arch Int Med 1991; 151:760 ± 4. Kreuning J, Bosm an FT, Kuiper G , Wal AM , Lindeman J. G astric and duodenal m ucosa in healthy individuals. J Clin Pathol 1978;31:69 ± 77. Toukan AU, Kamal MF, Am r SS, Arnaout M S, Abu-Romiyeh AS. Gastroduodenal in¯ ammation in patients w ith non-ulcer dyspepsia. Dig Dis Sci 1985;30:3 13 ± 20. Lambert JR, Borromeo M , Kormam M G, Hansky J. Role of Campylobacter pyloridis in non-ulcer dyspepsia: a randomized controlled trial. G astroenterology 1987;92:14 88. Borody T, Daskalopoulos G, Brandl S, Carrick J, H azell S. Dyspeptic symptoms improve following eradication of gastric Cam pylobacter pyloridis. G astroenterology 1987;92:13 24. Rokkas T, Pursey C, U zoechina E et al. Nonulcer dyspepsia and short term De-Nol therapy: a placebo controlled trial with particular reference to the role of Cam pylobacter pylori. G ut 1988;29: 1386 ± 91. M cNulty CA, G earty JC, Crump B et al. Campylobacter pyloridis and associated gastritis: investigatorblind, placebo controlled trial of bism uth salicylate and erythromycin ethylsuccinate. Br Med J 1986; 293:645 ± 9. G lupczynski Y, Burette A, Labbe M , Deprez C, DeReuck M, Deltenre M. Campylobacter pyloridisassociated gastritis: a double blind placebo controlled trial with amoxicillin. Am J Gastroenterol 1988;83:3 65 ± 71. Loþ eld RJFL , Potters H VHP, Stobberingh E, Flending JA, Van Spreeuwel JP, Arends JW. Cam pylobacter pyloridis associated gastritis in patients w ith non-ulcer dyspepsia: a double blind placebo controlled trial with colloidal bismuth subcitrate. G ut 1989;30:1 206 ± 12. Cutler AF, H avstad S, Ma CK, Blaser MJ, PerezPerez G I, Schuber t TT. Accuracy of invasive and noninvasive tests to diagnose Helicobacter pylori infection. Gastroenterology 1995;109: 136 ± 41. M archildon PA, Ciota LM , Zamaniyan FZ, Peacock JS, Graham DY. Evaluation of three comm ercial enzyme immunoassays compared with the 13 C urea breath test for detection of Helicobacter pylori infection. J Clin Microbiol 1996;34:11 47 ± 52. 13 Slomianski A, Schubert T, Cutler AF. [ C] U rea breath test to con® rm eradication of Helicobacter pylori. Am J Gastroenterol 1995;90:22 4 ± 6. Klein PD, Malaty HM , M artin RF, G raham KS, G enta RM , G raham DY. Noninvasive detection of H elicobacter pylori infection in clinical practice: the 13 C urea breath test. Am J G astroenterol 1996;91: 690 ± 4. Ag re us L, Talley N. Challenges in managing

Alcoholic gastritis dyspepsia in general practice. Br Med J 1997;315: 1284 ± 8. 91. American G astroenterological Association. Am erican G astroenterological Association m edical position statement: evaluation of dyspepsia. G astroenterology 1998;114: 579 ± 81. 92. American G astroenterological Association. AGA technical review: evaluation of dyspepsia. Gastroenterology 1998;114: 582 ± 95.


93. European Helicobacter Pylori Study G roup (EH PSG). Current European concepts in the m anagement of H elicobacter pylori infection. The M aastricht Consensus Repor t. G ut 1997;41:8 ± 13. 94. NIH Consensus Conference. Helicobacter pylori in peptic ulcer disease. NIH Consensus Development Panel on H elicobacter pylori in peptic ulcer disease. JAM A 1994;272:6 5 ± 9.

Gastritis in the alcoholic: relationship to gastric alcohol metabolism and Helicobacter pylori.

Chronic gastritis is common in the alcoholic. It is characterized by histological inflammation of the gastric mucosa and is associated with variable s...
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