Digestive Diseases and Sciences, Vol. 36, No. 7 (July 1991), pp. 917-923
Gastrointestinal Transit of Solid-Liquid Meal in Chronic Alcoholics M. WEGENER, MD, J. SCHAFFSTEIN, MD, U. DILGER, C. COENEN, MD, B. WEDMANN, MD, and G. SCHMIDT, MD
Gastric emptying, mouth-to-cecum transit, and whole-gut transit o f a solid-liquid meal were measured in 46 chronic alcoholics and in 30 control subjects by using scintigraphic techniques, hydrogen breath test, and stool markers. In the alcoholics various parameters such as ethanol consumption, gastrointestinal symptoms, and alcoholic neuropathy were determined and related to gastrointestinal transit times. Although there was no significant overall difference o f gastric emptying, abnormally delayed gastric emptying was detected in 23.9% o f the alcoholics but no control subject (P < 0.005). Mouth-to-cecum transit was significantly prolonged in the alcoholics (P < 0.001) with 14 alcoholics (37.8%) disclosing delayed mouth-to-cecum transit. No significant differences between both groups were detected concerning whole gut transit. In the alcoholics there was a significant correlation o f dyspeptic symptoms with delayed gastric emptying (P < 0.006), and alcoholics with diarrhea had an accelerated mouth-to-cecum transit as compared to those without diarrhea (P < 0.05). Neither the presence o f autonomic or peripheral neuropathy nor the presence o f liver cirrhosis or ascites was significantly related to gastrointestinal transit times. However, the daily ethanol ingestion significantly correlated with gastric emptying (P < 0.005). It is concluded, therefore, that in chronic alcoholics the small intestine and the stomach are most likely to be affected by gastrointestinal transit disorders and that these transit abnormalities are potentially related to toxic damage o f gastrointestinal smooth muscle. KEY WORDS: gastric emptying; mouth-to-cecum transit; whole-gut transit; chronic alcoholism.
After gastrointestinal absorption, ethanol as a polar substance is easily distributed by diffusion throughout all body water and may adversely affect every organ system in the body (1). However, the gastrointestinal tract as the absorptive canal and thus as the primary organ to come into contact with the ingested alcohol is faced with the highest initial concentrations of ethanol (2). To now, the influence Manuscript received July 30, 1990; revised manuscript received October 29, 1990; accepted October 29, 1990. From the Departments of Medicine and Radiology, St. JosefHospital, Ruhr-University Bochum, Bochum, Germany. This study was supported by a financial grant from Paul-KuthStiftung. Address for reprint requests: Dr. Martin Wegener, Department of Medicine, St. Josef-Hospital, Ruhr-University Bochum, Gudrunstrasse 56, 4630 Bochum, Germany.
of acute and chronic ethanol consumption on gastrointestinal motility remains poorly understood (3). A number of studies have focused almost exclusively on the effects of acute ethanol administration on upper gastrointestinal motility, and both esophageal and gastric motor dysfunction have been reported after acute alcoholism ingestion (2, 4, 5). However, there is a considerable dearth of information on the extent and origin of gastrointestinal motor dysfunction in all segments of the gut related to chronic alcohol abuse. We therefore undertook a prospective study to assess: (1) the effects of chronic alcoholism on gastrointestinal transit in different portions of the gut applying noninvasive techniques, such as radionuclide imaging, hydrogen breath tests, and stool
Digestive Diseases and Sciences, Vol. 36, No. 7 (July 1991)
0163-2116/91/0700-0917506.50/09 1991PlenumPublishingCorporation
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WEGENER ET AL markers; and (2) the relationship of gastrointestinal transit disorders with gastrointestinal symptoms and autonomic and peripheral neuropathy.
MATERIALS AND METHODS Subjects. A total of 46 consecutive alcoholics (8 female, 38 male; mean age 45.2 years, range 27-79 years; 32 smokers, 14 nonsmokers) and 30 healthy volunteers without significant gastrointestinal symptoms (14 female, 16 male; mean age 47.9 years, range 18-79 years; 13 smokers, 17 nonsmokers) were included in the study. There was no significant difference in mean body weight of both groups. Excluded were all alcoholics with a history or endoscopically proven peptic ulcer disease: laboratory (including determination of stool chymotrypsin activity), sonographic, or clinical evidence of pancreatic, biliary tract, and other gastrointestinal diseases (eg, chronic inflammatory bowel disease); a past history of gastrointestinal tract surgery (except appendectomy and cholecystectomy); serious systemic disorders (infections, malignancies); and other disorders known to affect gastrointestinal motility (diabetes mellitus, collagen vascular diseases). The control group consisted of 17 members of the clinical staff and 13 inpatients hospitalized because of minor complaints like joint distortions and intended removal of the menisci (N = 9), relapsing urticaria (N = 2), transitory supraventricular tachycardia (after exclusion of hyperthryoidism and autonomic adenoma) (N = 1), and chronic venous stasis of the lower extremities (N = 1). All alcoholics were inpatients hospitalized for detoxification (N = 24), alcoholic liver cirrhosis (N = 9), deranged liver function tests (N = 5), peripheral neuropathy (N = 4), and cerebral convulsions (N = 4). The history of drinking was obtained using a special questionnaire elucidating the duration and the daily amount of ethanol consumption. Whenever possible, additional information obtained from relatives was included. A history of drinking of at least 50 g ethanol dally for five years and lack of an abstinence period of at least six months during the last five years were the inclusion criteria for this study. The mean duration of regular alcohol consumption was 13.9 years (range 6-35 years) with a mean daily ethanol consumption of 165.5 g (range 50-700 g/day). Abdominal ultrasound was performed in all alcoholics and showed ascites in six patients and signs of chronic parenchymal liver disease in 24 patients. Endoscopy of the upper gastrointestinal tract was performed in 14 alcoholics because of dyspeptic symptoms or search for esophageal varices and revealed patchy or diffuse gastric erythema in four patients, esophageal varices in three patients, and intramural pseudodiverticulosis of the esophagus in one patient. Thirty-six alcoholics had an elevated 3,-glutamyl transferase and 19 had elevated transaminases. In 13 patients clinical (eg, ascites) and/or laboratory signs of liver cirrhosis were found. Histologic or macroscopic (laparoscopy) evidence of liver cirrhosis was obtained in 11 of these 13 patients. All alcoholics were studied after a minimum period of seven days after beginning the inpatient alcohol detoxification program
918
and not before at least three days after withdrawal of sedative medications administered for severe withdrawal symptoms. The average period between hospitalization and transit studies was 16.5 days. All other medications were discontinued at least 24 hr before the transit investigations. None of the patients had deranged serum electrolytes or severe withdrawal symptoms on the day of the transit test. Informed consent was obtained in all cases, and the study was approved by the ethics committee of the Ruhr-University Bochum. Prior to the transit studies, the presence of chronic gastrointestinal symptoms was assessed based on a standardized protocol. Symptoms, including retrosternal pain, epigastric pain, epigastric fullness, belching, nausea and vomiting, and abdominal pain were rated on a fourpoint scale as follows: 0 = not present, 1 = modest or rare, 2 = moderate, and 3 = severe or frequent disturbances. These six symptoms were analyzed separately and in combination as dyspeptic symptoms. As each symptom was scored from 0 to 3, the maximum possible total score of these six dyspeptic symptoms was 18. Diarrhea was defined as three or more loose stools per day and constipation as passing less than three spontaneous bowel actions per week. Of the 46 alcoholics eight complained of retrostemal pain (17.4%), 14 of epigastric pain (30.4%), 19 of epigastric fullness (41.3%), 20 of belching (43.5%), 22 of nausea and vomiting (47.8%), and 11 of abdominal pain (23.9%). Fifteen alcoholics (32.6%) had a score of dyspeptic symptoms of 4 or more (Figure 4 below). Twelve alcoholics suffered from diarrhea while drinking actively (26.1%), and six patients had constipation (13.0%) (Figure 3 below). The presence or absence of autonomic nerve dysfunction of the cardiovascular system was evaluated by four standard cardiovascular reflex tests (6), while symptomatic peripheral neuropathy were determined by a separate questionnaire and nerve conduction studies. Details of these tests have already been published (7). Of the 46 alcoholics, 18 (39.1%) had evidence of autonomic neuropathy, 13 (28.2%) of whom had two abnormal cardiovascular reflex tests, four (8.7%) had three abnormal tests, and one (2.2%) had four abnormal tests. Eight alcoholics (17.4%) suffered from symptomatic peripheral neuropathy, six of whom had additional evidence of autonomic nerve dysfunction.
Gastric Emptying, Mouth-to-Cecum Transit (MCT) and Whole-Gut Transit (WGT). After a 15-hr fast and a nicotine-free period of 15 hr all subjects were given a standardized 375 g meal containing 45 g wheat bread, two scrambled eggs (130 g), 100 ml coffee, and 100 ml unsweetened orange juice. The coffee contained 0.5 mCi 99mTc colloid, and 10 g lactulose (Bifiteral, Duphar Pharma GmbH, Hannover, Germany) was added to the orange juice. Both were ingested at the end of the meal and three capsules each containing 250 mg indigo carmine were swallowed. The gastrointestinal transit tests were performed as described previously (7, 8). In short, gastric emptying was measured in supine position by an anterior gamma camera recording radionuclide counts over a total period of 60 min. At the end of the data acquisition, 0.1 mCi 99mTc colloid was given orally and a 1-min left lateral Digestive Diseases and Sciences, Vol. 36, No. 7 (July 1991)
GASTROINTESTINAL TRANSIT IN CHRONIC ALCOHOLICS image of the upper abdomen was obtained to correct for attenuation (9). Using a computer, time-activity curves were calculated and, after correction for isotope decay and attenuation, the percentage remaining in the stomach at 60 min (ret 60 min) after meal completion was obtained from these plots. MCT time as a parameter of small intestinal transit was assessed by the hydrogen breath test. For calculation of MCT, the first sustained increase of breath hydrogen concentration ->20 ppm or ->10 ppm in patients without any increase of breath hydrogen concentration ->20 ppm was used as a cutoff point. In patients with short MCT (---30 min) and/or diarrhea, 50 g glucose in 300 ml water was given orally on a separate day to detect small intestinal bacterial overgrowth. A sustained rise of breath hydrogen concentration ->20ppm in the first 120 min after ingestion of the glucose was considered as evidence of small intestinal bacterial overgrowth. WGT time, largely reflecting large intestinal transit time, was determined by the first appearance of the indigo carmine in the stool. Subjects were instructed to inspect each separate stool motion for the presence of blue discoloration. Statistical analysis.All data were entered onto a computer data base and analyzed, as appropriate, by Wilcoxon's rank sum test, • analysis, Fisher's exact test (when the expected number in any cell of 2 x 2 tables was less than 5), Duncan's test for multiple comparisons, and the Spearman rank-correlation coefficient. Gastric emptying, MCT, and WGT times were considered different from normal when they fell outside - 2 SDfrom the mean of the control group.
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RESULTS Gastric Emptying. There was a trend towards delayed gastric emptying in alcoholics as compared to controls, but this difference failed to reach clinical significance (P < 0.075, Figure 1). However, the proportion of subjects with abnormally delayed gastric emptying (ret 60 min > 80%) was significantly larger in the alcoholics (N = 1I, 23.9%) as compared to the control group (N = 0) (P < 0.005) (Figure 1).
Mouth-to-Cecum Transit (MCT) and Whole-Gut Transit (WGT). MCT as indicated by a sustained rise of breath hydrogen was measured in 37 alcoholics and 28 controls only, as in seven alcoholics and two controls no increase of hydrogen excretion of at least 10 ppm was detected in a period of 300 min after meal ingestion. Two additional alcoholics (with diarrhea) had evidence of small intestinal bacterial overgrowth, indicated by a rapid rise of breath hydrogen concentration during the first 30 min after ingestion of the test meal and after further administration of glucose. MCT was significantly delayed in alcoholics as compared to the control Digestive Diseases and Sciences, Vol. 36, No. 7 (July 1991)
Controls Alcoholics n=30 n=46 Fig 1. Gastric emptying data of controls and alcoholics, expressed as the percentage of gastric retention at 60 rain (ret 60 min) (P = 0.075). Median values also are presented. Upper limit of the normal range (dotted line): ret 60 min = 80%, P < 0.005 for the proportion of abnormally delayed emptying values among alcoholics (23.9%) versus controls (0%).
group (P < 0.001) with 14 alcoholics (37.8%) and one control (3.6%) disclosing abnormally prolonged MCT (> 147 min, Figure 2). Since four of these 14 alcoholics (28.6%) with prolonged MCT also had delayed gastric emptying, prolonged MCT in these four alcoholics might partly be due to delayed gastric emptying. When excluding these four alcoholics, the proportion of subjects with abnormally prolonged MCT was still significantly larger in the alcoholics (27.0%) as compared to the control group (3.6%) (P < 0.01). There was no significant overall difference of WGT as defined by the first stool passage of indigocarmine in the alcoholics and the control group (P = 0.454). No alcoholic and one control had prolonged WGT (> 34 h. Figure 3).
919
WEGENER ET AL 50
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Fig 2. Mouth-to-cecum transit (MCT) in minutes in controls and alcoholics ( P < 0 . 0 0 1 ) . Median values are indicated. Upper limit of the normal range (dotted line) = 147 m i n , P < 0 . 0 0 1 for the proportion of alcoholics with abnormally prolonged MCT ( 3 7 . 8 % ) versus controls ( 3 . 6 % ) . S o l i d circles represent alcoholics without diarrhea, open circles represent alcoholics with diarrhea.
Gastrointestinal Transit and Symptoms. Of the various symptoms related to the upper gastrointestinal tract, the severity of "epigastric fullness" significantly correlated with gastric emptying (R = 0.53, P < 0.0002). Moreover a significant correlation was observed between gastric emptying and the total score of dyspeptic symptoms (R = 0.48, P < 0.006, Figure 4). Two of 12 alcoholics with diarrhea had evidence of small intestinal bacterial overgrowth, and two had no significant rise of breath hydrogen concentration after ingestion of the test meal. In the other eight alcoholics with diarrhea, MCT was significantly accelerated (median = 80 min) as a compared to alcoholics without diarrhea (median = 140 min; P < 0.05) but not as compared to the control group (median = 80 min; P > 0.05) (Figure 2). Alcoholics with constipation had a significantly prolonged WGT (median = 21.9 hr) as compared to alcoholics without constipation
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Fig 3. Whole-gut transit (WGT) in controls and alcoholics including median values ( P = 0 . 1 4 7 ) . Upper limit of the normal range (dotted l i n e ) = 3 4 h r , P = 0 . 4 5 4 for the proportion of abnormally prolonged WGT among alcoholics (0%) and controls ( 3 . 6 % ) . S o l i d circles represent alcoholic without constipation, open circles represent alcoholics with constipation.
(median = 8.4 hr) and the control group (median = 11.9 hr, P < 0.05) (Figure 2). Other Alcohol-Associated Complications, Ethanol Consumption, and Gastrointestinal Transit. When alcoholics with autonomic neuropathy (->2 abnormal tests) were compared to those without autonomic neuropathy, neither gastric emptying (P = 0.338), MCT (P = 0.678), nor WGT (P = 0.804) were significantly different in both groups, and the same applies to symptomatic peripheral neuropathy (gastric emptying: P = 0.151; MCT: P = 0.716; WGT: P = 0.632). Likewise, there was no significant correlation between the score for autonomic neuropathy defined as the number of abnormal tests and gastric emptying (R = 0.19, P = 0.211), MCT (R = - 0 . 0 8 , P = 0.589), or WGT (R = - 0 . 0 7 , P = 0.639). Neither the presence of liver cirrhosis ( N = 13) nor the existence of ascites ( N = 6) had any significant influence on gastric emptying (P = 0.999 and 0.396), MCT (P = 0.864 and 0.238), or WGT (P Digestive Diseases and Sciences, VoL 36, No. 7 (July 1991)
GASTROINTESTINAL TRANSIT IN CHRONIC ALCOHOLICS 9
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Fig 4. The relationshipbetweengastricemptying(ret 60 min)and the dyspepticsymptomscore in alcoholics(R = 0.48, P < 0.005). The dotted line separates normal from abnormally delayed gastric emptying. = 0.137 and 0.889). However, concerning regular ethanol ingestion a significant correlation between gastric emptying and the mean daily ethanol consumption was observed in the alcoholics (R = 0.417, P < 0.005) (Figure 5). No such correlation was observed for MCT (R = 0.072, P = 0.635) and WGT (R = 0.105, P = 0.486). DISCUSSION Several studies have demonstrated that acute ethanol administration may result in a significant decrease of esophageal peristalsis of lower esophageal sphincter pressure (10, 11), whereas investigations of chronic alcohol administration on esophageal motility have yielded inconsistent results (12, 13). Concerning gastric function it has been shown that acute peroral administration of ethanol delays gastric emptying in healthy subjects (3, 14, 15). Referring to chronic alcohol ingestion, only scarce data from animal experimental studies are available suggesting that chronic ethanol exposure profoundly inhibits gastric emptying in cats (16). The present study is the first extensive evaluation of gastrointestinal transit of a physiologic lactulose supplemented test meal through the stomach, the Digestive Diseases and Sciences, Vol. 36, No. 7 (July 1991)
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small intestine (MCT), and the colon (largely reflected by WGT) in chronic alcoholics. It has to be mentioned that there was a higher prevalence of males and smokers in the study group as compared to the controls. However, smoking was stopped 15 hr prior to the transit studies and, apart from gastric emptying, a significant influence of sex on gastrointestinal transit times has not been demonstrated. As to gastric emptying, this disparity in sex would - - if at all - - tend to lessen the differences between alcoholics and controls as gastric emptying has been shown to be significantly slower in women than in men (17). The majority of the alcoholics had a long history of alcohol abuse, and there was a considerable prevalence of neuropathic and hepatic complications, including hepatic cirrhosis. Although there was no significant overall difference of gastric emptying rates between the alcoholics and the controls, abnormally delayed gastric emptying was detected in 11 alcoholics (23.9%) as compared to none in the control subjects. With respect to this prolongation of gastric emptying in a subgroup of alcoholics, there was a weak but significant correlation between these gastric emptying disorders and the dyspeptic symptom score, particularly the sensation of epigastric fullness. 921
WEGENER ET AL Concerning intestinal dysfunction, it has been noted previously that diarrhea is a frequent symptom in alcoholics (1-3). Corresponding to these data, about one quarter of the alcoholics (N = 12, 26.1%) in the present study complained of diarrhea while drinking actively. Apart from reducing net intestinal absorption of water and electrolytes, acute ethanol administration has been shown to enhance propulsive contractions in the ileum and to suppress impeding contractions in the jejunum (18), which both might enhance small intestinal transit and thus contribute to diarrhea. In the present study mouth-to-cecum transit, largely reflecting small intestinal transit, was significantly shorter in eight alcoholics with diarrhea as compared to those without diarrhea, but did not differ form MCT in the control group. These results are consistent with previously published data demonstrating significantly shortened MCT times in alcoholics while actively drinking (19, 20), which increased to values not significantly different from normal controls after 8-10 days of abstinence (20). The most striking feature of the present study was, however, a significant prolongation of overall MCT times in the alcoholics as compared to the control group. These data corroborate results of a recently performed MCT study in patients with alcoholic and nonalcoholic cirrhosis giving evidence of a significant delay of MCT in patients with alcoholic cirrhosis (21). However, as gastric emptying was not measured in this study, the prolonged MCT values might have reflected simply a delay in gastric emptying. In our study abnormally slow MCT was detected in 14 of 37 alcoholics (37.8%), four of whom (28.6%) had delayed gastric emptying as well. Thus delayed gastric emptying may partly account for prolonged MCT in about a quarter of alcoholics with increased MCT times. Apart from results indicating a possible inhibition of rectosigmoid motility induced by acute ethanol administration (22), there is a lack of information on the effects of alcohol ingestion on colonic motor function. Our data do not reveal any difference of whole gut transit (WGT) time, largely reflecting colonic transit, in the alcoholics and the control subjects. As WGT was estimated with a relatively crude method--measuring the appearance time of the test meal in the stool this study may well have failed to detect subtle disorders of colonic motor function. In the alcoholics the presence of constipation was related to prolonged MCT as compared
922
to alcoholics without constipation and the control subjects. The causal factors of these observed gastric emptying and small intestinal transit disorders in chronic alcoholics remain to be elucidated. While the influence of factors related to the withdrawal phase cannot be excluded totally, our data do not suggest that the presence of hepatic cirrhosis or ascites has any effect on gastrointestinal transit times. Moreover neither abnormal gastric emptying nor abnormal MCT were related to autonomic or peripheral neuropathy. In fact, it has been demonstrated recently that esophageal motor dysfunction in chronic alcoholics is likewise independent of autonomic and peripheral neuropathy (13). This, however, does not rule out that alcohol-induced neuropathic damage might occur independently in different organs such as the enteric nervous system and the cardiovascular or the peripheral nerve system, and it should be stressed that in the present study autonomic function tests were limited to the cardiovascular system. Previous animal experimental and human studies have yielded strong evidence that alcohol is a muscle toxin that is toxic to striated muscle in a dose-dependent manner, producing a considerable frequency of cardiomyopathy and myopathy of skeletal muscle in chronic alcoholics (23, 24). It is thus tempting to speculate whether toxic damage of gastrointestinal smooth muscle is the underlying mechanism of gastrointestinal transit disorders in chronic alcoholism. The significant correlation of mean daily ethanol consumption and gastric emptying observed in this study may indicate that - - at least concerning gastric smooth muscle motor function m this ethanol-induced damage might be dosedependent. REFERENCES 1. Geokas MC, Lieber CS, French S, Halsted CH: Ethanol, the liver, and the gastrointestinal tract. Ann Intern Med 95:198211, 1981 2. Burbige EJ, Lewis DR, Halsted CH: Alcohol and the gastrointestinal tract. Med Clin North Am 68:77-89, 1984 3. Van Thiel DH, Lipsitz HD, Porter LE, Schade RR, Gottlieb GP, Graham TO: Gastrointestinal and hepatic manifestations of chronic alcoholism. Gastroenterology 81:594-615, 1981 4. Kjellen G, Tibbling L: Influence of body position, dry and water swallows, smoking, and alcohol on esophageal acid cleating. Scand J Gastroenterol 13:283-288, 1978 5. Kaufman SE, Kaye MD: Induction of gastro-oesophageal reflux by alcohol. Gut 19:336-338, 1978 Digestive Diseases and Sciences, Vol. 36, No. 7 (July 1991)
G A S T R O I N T E S T I N A L T R A N S I T IN C H R O N I C A L C O H O L I C S 6. Ewing DJ, Clarke BF: Diagnosis and management of diabetic autonomic neuropathy. Br Med J 285:916-918, 1982 7. Wegener M, B6rsch G, Schaffstein J, Luerweg C, Leverkus F: Gastrointestinal transit disorders in patients with insulintreated diabetes mellitus. Dig Dis 8:23-36, 1990 8. Wegener M, BOrsch G, Schaffstein J, Reuter C, Leverkus F: Frequency of idiopathic gastric stasis and intestinal transit disorders in essential dyspepsia. J Clin Gastroenterol 11:163-168, 1989 9. Collins PJ, Horowitz M, Cook DJ, Harding PE, Shearman DJC: Gastric emptying in normal subjects--a reproducible technique using a single scintillation camera and computer system. Gut 24:1117-1125, 1983 10. Mayer EM, Grabowski CJ, Fisher RS: Effects of graded doses of alcohol upon esophageal motor function. Gastroenterology 75:1133-1136, 1978 11. Keshavarzian A, Polepollo C, Iber FL, Durkin M, Morrissey M: Effect of acute and chronic ethanol on esophageal motility. Gastroenterology 95:A874, 1988 12. Silver LS, Worner TM, Korsten MA: Esophageal function in chronic alcoholics. Am J Gastroenterol 81:423-426, 1986 13. Keshavarzian A, Iber FL, Fergusson Y: Esophageal manometry and radionuclide emptying in chronic alcoholics. Gastroenterology 92:651-657, 1987 14. Barboriak JJ, Meade RC: Effect of alcohol on gastric emptying in man. Am J Clin Nutr 23:1151-1153, 1970
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15. Cooke AR: Ethanol and gastric function. Gastroenterology 62:501-502, 1972 16. Willson CA, Bushnell D, Keshavarzian A: The effect of acute and chronic ethanol administration on gastric emptying in cats. Dig Dis Sci 35:444-448, 1990 17. Hutson WR, Roehrkasse RL, Wald A: Influence of gender and menopause on gastric emptying and motility. Gastroenterology 96:11-17, 1989 18. Robles EA, Mezey E, Halsted CH, Schuster MM: Effect of ethanol on motility of the small intestine. Hopkins Med J 135:17-24, 1974 19. Ghimirie M, Morris AI, Hill D, Brownless SM, Stockdale HR, Patten MD: A mechanism for diarrhea in alcoholics. Gastroenterology 88:A1392, 1985 20. Keshavarzian A, Iber FL, Dangleis MD, Cornish R: Intestinal transit and lactose intolerance in chronic alcoholics. Am J Clin Nutr 44:70-76, 1986 21. Hiippe D, T6nissen R, Hofius M, Kuntz HD, May B: Influence of chronic alcoholism and liver cirrhosis on oro-cecal transit (H2 breath test). Z Gastroenterol 27:624-628, 1989 22. Berenson MM, Avner DL: Alcohol inhibition of rectosigmoid motility in humans. Digestion 22:210-215, 1981 23. Inoue F, Frank GB: Effects of ethyl alcohol on excitability and on neuromuscular transmission in frog skeletal muscle. Br J Pharmacol Chemother 30:186-193, 1967 24. Urbano-Marquez A, Estruch R, Navarro-Lopez F, Grau JM, Mont L, Rubin E: The effects of alcoholism on skeletal and cardiac muscle. N Engl J Med 320:409-415, 1989
923
Gastrointestinal Transit of Solid-Liquid Meal in Chronic Alcoholics M. WEGENER, MD, J. SCHAFFSTEIN, MD, U. DILGER, C. COENEN, MD, B. WEDMANN, MD, and G. SCHMIDT, MD
Gastric emptying, mouth-to-cecum transit, and whole-gut transit o f a solid-liquid meal were measured in 46 chronic alcoholics and in 30 control subjects by using scintigraphic techniques, hydrogen breath test, and stool markers. In the alcoholics various parameters such as ethanol consumption, gastrointestinal symptoms, and alcoholic neuropathy were determined and related to gastrointestinal transit times. Although there was no significant overall difference o f gastric emptying, abnormally delayed gastric emptying was detected in 23.9% o f the alcoholics but no control subject (P < 0.005). Mouth-to-cecum transit was significantly prolonged in the alcoholics (P < 0.001) with 14 alcoholics (37.8%) disclosing delayed mouth-to-cecum transit. No significant differences between both groups were detected concerning whole gut transit. In the alcoholics there was a significant correlation o f dyspeptic symptoms with delayed gastric emptying (P < 0.006), and alcoholics with diarrhea had an accelerated mouth-to-cecum transit as compared to those without diarrhea (P < 0.05). Neither the presence o f autonomic or peripheral neuropathy nor the presence o f liver cirrhosis or ascites was significantly related to gastrointestinal transit times. However, the daily ethanol ingestion significantly correlated with gastric emptying (P < 0.005). It is concluded, therefore, that in chronic alcoholics the small intestine and the stomach are most likely to be affected by gastrointestinal transit disorders and that these transit abnormalities are potentially related to toxic damage o f gastrointestinal smooth muscle. KEY WORDS: gastric emptying; mouth-to-cecum transit; whole-gut transit; chronic alcoholism.
After gastrointestinal absorption, ethanol as a polar substance is easily distributed by diffusion throughout all body water and may adversely affect every organ system in the body (1). However, the gastrointestinal tract as the absorptive canal and thus as the primary organ to come into contact with the ingested alcohol is faced with the highest initial concentrations of ethanol (2). To now, the influence Manuscript received July 30, 1990; revised manuscript received October 29, 1990; accepted October 29, 1990. From the Departments of Medicine and Radiology, St. JosefHospital, Ruhr-University Bochum, Bochum, Germany. This study was supported by a financial grant from Paul-KuthStiftung. Address for reprint requests: Dr. Martin Wegener, Department of Medicine, St. Josef-Hospital, Ruhr-University Bochum, Gudrunstrasse 56, 4630 Bochum, Germany.
of acute and chronic ethanol consumption on gastrointestinal motility remains poorly understood (3). A number of studies have focused almost exclusively on the effects of acute ethanol administration on upper gastrointestinal motility, and both esophageal and gastric motor dysfunction have been reported after acute alcoholism ingestion (2, 4, 5). However, there is a considerable dearth of information on the extent and origin of gastrointestinal motor dysfunction in all segments of the gut related to chronic alcohol abuse. We therefore undertook a prospective study to assess: (1) the effects of chronic alcoholism on gastrointestinal transit in different portions of the gut applying noninvasive techniques, such as radionuclide imaging, hydrogen breath tests, and stool
Digestive Diseases and Sciences, Vol. 36, No. 7 (July 1991)
0163-2116/91/0700-0917506.50/09 1991PlenumPublishingCorporation
917
WEGENER ET AL markers; and (2) the relationship of gastrointestinal transit disorders with gastrointestinal symptoms and autonomic and peripheral neuropathy.
MATERIALS AND METHODS Subjects. A total of 46 consecutive alcoholics (8 female, 38 male; mean age 45.2 years, range 27-79 years; 32 smokers, 14 nonsmokers) and 30 healthy volunteers without significant gastrointestinal symptoms (14 female, 16 male; mean age 47.9 years, range 18-79 years; 13 smokers, 17 nonsmokers) were included in the study. There was no significant difference in mean body weight of both groups. Excluded were all alcoholics with a history or endoscopically proven peptic ulcer disease: laboratory (including determination of stool chymotrypsin activity), sonographic, or clinical evidence of pancreatic, biliary tract, and other gastrointestinal diseases (eg, chronic inflammatory bowel disease); a past history of gastrointestinal tract surgery (except appendectomy and cholecystectomy); serious systemic disorders (infections, malignancies); and other disorders known to affect gastrointestinal motility (diabetes mellitus, collagen vascular diseases). The control group consisted of 17 members of the clinical staff and 13 inpatients hospitalized because of minor complaints like joint distortions and intended removal of the menisci (N = 9), relapsing urticaria (N = 2), transitory supraventricular tachycardia (after exclusion of hyperthryoidism and autonomic adenoma) (N = 1), and chronic venous stasis of the lower extremities (N = 1). All alcoholics were inpatients hospitalized for detoxification (N = 24), alcoholic liver cirrhosis (N = 9), deranged liver function tests (N = 5), peripheral neuropathy (N = 4), and cerebral convulsions (N = 4). The history of drinking was obtained using a special questionnaire elucidating the duration and the daily amount of ethanol consumption. Whenever possible, additional information obtained from relatives was included. A history of drinking of at least 50 g ethanol dally for five years and lack of an abstinence period of at least six months during the last five years were the inclusion criteria for this study. The mean duration of regular alcohol consumption was 13.9 years (range 6-35 years) with a mean daily ethanol consumption of 165.5 g (range 50-700 g/day). Abdominal ultrasound was performed in all alcoholics and showed ascites in six patients and signs of chronic parenchymal liver disease in 24 patients. Endoscopy of the upper gastrointestinal tract was performed in 14 alcoholics because of dyspeptic symptoms or search for esophageal varices and revealed patchy or diffuse gastric erythema in four patients, esophageal varices in three patients, and intramural pseudodiverticulosis of the esophagus in one patient. Thirty-six alcoholics had an elevated 3,-glutamyl transferase and 19 had elevated transaminases. In 13 patients clinical (eg, ascites) and/or laboratory signs of liver cirrhosis were found. Histologic or macroscopic (laparoscopy) evidence of liver cirrhosis was obtained in 11 of these 13 patients. All alcoholics were studied after a minimum period of seven days after beginning the inpatient alcohol detoxification program
918
and not before at least three days after withdrawal of sedative medications administered for severe withdrawal symptoms. The average period between hospitalization and transit studies was 16.5 days. All other medications were discontinued at least 24 hr before the transit investigations. None of the patients had deranged serum electrolytes or severe withdrawal symptoms on the day of the transit test. Informed consent was obtained in all cases, and the study was approved by the ethics committee of the Ruhr-University Bochum. Prior to the transit studies, the presence of chronic gastrointestinal symptoms was assessed based on a standardized protocol. Symptoms, including retrosternal pain, epigastric pain, epigastric fullness, belching, nausea and vomiting, and abdominal pain were rated on a fourpoint scale as follows: 0 = not present, 1 = modest or rare, 2 = moderate, and 3 = severe or frequent disturbances. These six symptoms were analyzed separately and in combination as dyspeptic symptoms. As each symptom was scored from 0 to 3, the maximum possible total score of these six dyspeptic symptoms was 18. Diarrhea was defined as three or more loose stools per day and constipation as passing less than three spontaneous bowel actions per week. Of the 46 alcoholics eight complained of retrostemal pain (17.4%), 14 of epigastric pain (30.4%), 19 of epigastric fullness (41.3%), 20 of belching (43.5%), 22 of nausea and vomiting (47.8%), and 11 of abdominal pain (23.9%). Fifteen alcoholics (32.6%) had a score of dyspeptic symptoms of 4 or more (Figure 4 below). Twelve alcoholics suffered from diarrhea while drinking actively (26.1%), and six patients had constipation (13.0%) (Figure 3 below). The presence or absence of autonomic nerve dysfunction of the cardiovascular system was evaluated by four standard cardiovascular reflex tests (6), while symptomatic peripheral neuropathy were determined by a separate questionnaire and nerve conduction studies. Details of these tests have already been published (7). Of the 46 alcoholics, 18 (39.1%) had evidence of autonomic neuropathy, 13 (28.2%) of whom had two abnormal cardiovascular reflex tests, four (8.7%) had three abnormal tests, and one (2.2%) had four abnormal tests. Eight alcoholics (17.4%) suffered from symptomatic peripheral neuropathy, six of whom had additional evidence of autonomic nerve dysfunction.
Gastric Emptying, Mouth-to-Cecum Transit (MCT) and Whole-Gut Transit (WGT). After a 15-hr fast and a nicotine-free period of 15 hr all subjects were given a standardized 375 g meal containing 45 g wheat bread, two scrambled eggs (130 g), 100 ml coffee, and 100 ml unsweetened orange juice. The coffee contained 0.5 mCi 99mTc colloid, and 10 g lactulose (Bifiteral, Duphar Pharma GmbH, Hannover, Germany) was added to the orange juice. Both were ingested at the end of the meal and three capsules each containing 250 mg indigo carmine were swallowed. The gastrointestinal transit tests were performed as described previously (7, 8). In short, gastric emptying was measured in supine position by an anterior gamma camera recording radionuclide counts over a total period of 60 min. At the end of the data acquisition, 0.1 mCi 99mTc colloid was given orally and a 1-min left lateral Digestive Diseases and Sciences, Vol. 36, No. 7 (July 1991)
GASTROINTESTINAL TRANSIT IN CHRONIC ALCOHOLICS image of the upper abdomen was obtained to correct for attenuation (9). Using a computer, time-activity curves were calculated and, after correction for isotope decay and attenuation, the percentage remaining in the stomach at 60 min (ret 60 min) after meal completion was obtained from these plots. MCT time as a parameter of small intestinal transit was assessed by the hydrogen breath test. For calculation of MCT, the first sustained increase of breath hydrogen concentration ->20 ppm or ->10 ppm in patients without any increase of breath hydrogen concentration ->20 ppm was used as a cutoff point. In patients with short MCT (---30 min) and/or diarrhea, 50 g glucose in 300 ml water was given orally on a separate day to detect small intestinal bacterial overgrowth. A sustained rise of breath hydrogen concentration ->20ppm in the first 120 min after ingestion of the glucose was considered as evidence of small intestinal bacterial overgrowth. WGT time, largely reflecting large intestinal transit time, was determined by the first appearance of the indigo carmine in the stool. Subjects were instructed to inspect each separate stool motion for the presence of blue discoloration. Statistical analysis.All data were entered onto a computer data base and analyzed, as appropriate, by Wilcoxon's rank sum test, • analysis, Fisher's exact test (when the expected number in any cell of 2 x 2 tables was less than 5), Duncan's test for multiple comparisons, and the Spearman rank-correlation coefficient. Gastric emptying, MCT, and WGT times were considered different from normal when they fell outside - 2 SDfrom the mean of the control group.
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RESULTS Gastric Emptying. There was a trend towards delayed gastric emptying in alcoholics as compared to controls, but this difference failed to reach clinical significance (P < 0.075, Figure 1). However, the proportion of subjects with abnormally delayed gastric emptying (ret 60 min > 80%) was significantly larger in the alcoholics (N = 1I, 23.9%) as compared to the control group (N = 0) (P < 0.005) (Figure 1).
Mouth-to-Cecum Transit (MCT) and Whole-Gut Transit (WGT). MCT as indicated by a sustained rise of breath hydrogen was measured in 37 alcoholics and 28 controls only, as in seven alcoholics and two controls no increase of hydrogen excretion of at least 10 ppm was detected in a period of 300 min after meal ingestion. Two additional alcoholics (with diarrhea) had evidence of small intestinal bacterial overgrowth, indicated by a rapid rise of breath hydrogen concentration during the first 30 min after ingestion of the test meal and after further administration of glucose. MCT was significantly delayed in alcoholics as compared to the control Digestive Diseases and Sciences, Vol. 36, No. 7 (July 1991)
Controls Alcoholics n=30 n=46 Fig 1. Gastric emptying data of controls and alcoholics, expressed as the percentage of gastric retention at 60 rain (ret 60 min) (P = 0.075). Median values also are presented. Upper limit of the normal range (dotted line): ret 60 min = 80%, P < 0.005 for the proportion of abnormally delayed emptying values among alcoholics (23.9%) versus controls (0%).
group (P < 0.001) with 14 alcoholics (37.8%) and one control (3.6%) disclosing abnormally prolonged MCT (> 147 min, Figure 2). Since four of these 14 alcoholics (28.6%) with prolonged MCT also had delayed gastric emptying, prolonged MCT in these four alcoholics might partly be due to delayed gastric emptying. When excluding these four alcoholics, the proportion of subjects with abnormally prolonged MCT was still significantly larger in the alcoholics (27.0%) as compared to the control group (3.6%) (P < 0.01). There was no significant overall difference of WGT as defined by the first stool passage of indigocarmine in the alcoholics and the control group (P = 0.454). No alcoholic and one control had prolonged WGT (> 34 h. Figure 3).
919
WEGENER ET AL 50
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Fig 2. Mouth-to-cecum transit (MCT) in minutes in controls and alcoholics ( P < 0 . 0 0 1 ) . Median values are indicated. Upper limit of the normal range (dotted line) = 147 m i n , P < 0 . 0 0 1 for the proportion of alcoholics with abnormally prolonged MCT ( 3 7 . 8 % ) versus controls ( 3 . 6 % ) . S o l i d circles represent alcoholics without diarrhea, open circles represent alcoholics with diarrhea.
Gastrointestinal Transit and Symptoms. Of the various symptoms related to the upper gastrointestinal tract, the severity of "epigastric fullness" significantly correlated with gastric emptying (R = 0.53, P < 0.0002). Moreover a significant correlation was observed between gastric emptying and the total score of dyspeptic symptoms (R = 0.48, P < 0.006, Figure 4). Two of 12 alcoholics with diarrhea had evidence of small intestinal bacterial overgrowth, and two had no significant rise of breath hydrogen concentration after ingestion of the test meal. In the other eight alcoholics with diarrhea, MCT was significantly accelerated (median = 80 min) as a compared to alcoholics without diarrhea (median = 140 min; P < 0.05) but not as compared to the control group (median = 80 min; P > 0.05) (Figure 2). Alcoholics with constipation had a significantly prolonged WGT (median = 21.9 hr) as compared to alcoholics without constipation
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Fig 3. Whole-gut transit (WGT) in controls and alcoholics including median values ( P = 0 . 1 4 7 ) . Upper limit of the normal range (dotted l i n e ) = 3 4 h r , P = 0 . 4 5 4 for the proportion of abnormally prolonged WGT among alcoholics (0%) and controls ( 3 . 6 % ) . S o l i d circles represent alcoholic without constipation, open circles represent alcoholics with constipation.
(median = 8.4 hr) and the control group (median = 11.9 hr, P < 0.05) (Figure 2). Other Alcohol-Associated Complications, Ethanol Consumption, and Gastrointestinal Transit. When alcoholics with autonomic neuropathy (->2 abnormal tests) were compared to those without autonomic neuropathy, neither gastric emptying (P = 0.338), MCT (P = 0.678), nor WGT (P = 0.804) were significantly different in both groups, and the same applies to symptomatic peripheral neuropathy (gastric emptying: P = 0.151; MCT: P = 0.716; WGT: P = 0.632). Likewise, there was no significant correlation between the score for autonomic neuropathy defined as the number of abnormal tests and gastric emptying (R = 0.19, P = 0.211), MCT (R = - 0 . 0 8 , P = 0.589), or WGT (R = - 0 . 0 7 , P = 0.639). Neither the presence of liver cirrhosis ( N = 13) nor the existence of ascites ( N = 6) had any significant influence on gastric emptying (P = 0.999 and 0.396), MCT (P = 0.864 and 0.238), or WGT (P Digestive Diseases and Sciences, VoL 36, No. 7 (July 1991)
GASTROINTESTINAL TRANSIT IN CHRONIC ALCOHOLICS 9
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Fig 4. The relationshipbetweengastricemptying(ret 60 min)and the dyspepticsymptomscore in alcoholics(R = 0.48, P < 0.005). The dotted line separates normal from abnormally delayed gastric emptying. = 0.137 and 0.889). However, concerning regular ethanol ingestion a significant correlation between gastric emptying and the mean daily ethanol consumption was observed in the alcoholics (R = 0.417, P < 0.005) (Figure 5). No such correlation was observed for MCT (R = 0.072, P = 0.635) and WGT (R = 0.105, P = 0.486). DISCUSSION Several studies have demonstrated that acute ethanol administration may result in a significant decrease of esophageal peristalsis of lower esophageal sphincter pressure (10, 11), whereas investigations of chronic alcohol administration on esophageal motility have yielded inconsistent results (12, 13). Concerning gastric function it has been shown that acute peroral administration of ethanol delays gastric emptying in healthy subjects (3, 14, 15). Referring to chronic alcohol ingestion, only scarce data from animal experimental studies are available suggesting that chronic ethanol exposure profoundly inhibits gastric emptying in cats (16). The present study is the first extensive evaluation of gastrointestinal transit of a physiologic lactulose supplemented test meal through the stomach, the Digestive Diseases and Sciences, Vol. 36, No. 7 (July 1991)
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small intestine (MCT), and the colon (largely reflected by WGT) in chronic alcoholics. It has to be mentioned that there was a higher prevalence of males and smokers in the study group as compared to the controls. However, smoking was stopped 15 hr prior to the transit studies and, apart from gastric emptying, a significant influence of sex on gastrointestinal transit times has not been demonstrated. As to gastric emptying, this disparity in sex would - - if at all - - tend to lessen the differences between alcoholics and controls as gastric emptying has been shown to be significantly slower in women than in men (17). The majority of the alcoholics had a long history of alcohol abuse, and there was a considerable prevalence of neuropathic and hepatic complications, including hepatic cirrhosis. Although there was no significant overall difference of gastric emptying rates between the alcoholics and the controls, abnormally delayed gastric emptying was detected in 11 alcoholics (23.9%) as compared to none in the control subjects. With respect to this prolongation of gastric emptying in a subgroup of alcoholics, there was a weak but significant correlation between these gastric emptying disorders and the dyspeptic symptom score, particularly the sensation of epigastric fullness. 921
WEGENER ET AL Concerning intestinal dysfunction, it has been noted previously that diarrhea is a frequent symptom in alcoholics (1-3). Corresponding to these data, about one quarter of the alcoholics (N = 12, 26.1%) in the present study complained of diarrhea while drinking actively. Apart from reducing net intestinal absorption of water and electrolytes, acute ethanol administration has been shown to enhance propulsive contractions in the ileum and to suppress impeding contractions in the jejunum (18), which both might enhance small intestinal transit and thus contribute to diarrhea. In the present study mouth-to-cecum transit, largely reflecting small intestinal transit, was significantly shorter in eight alcoholics with diarrhea as compared to those without diarrhea, but did not differ form MCT in the control group. These results are consistent with previously published data demonstrating significantly shortened MCT times in alcoholics while actively drinking (19, 20), which increased to values not significantly different from normal controls after 8-10 days of abstinence (20). The most striking feature of the present study was, however, a significant prolongation of overall MCT times in the alcoholics as compared to the control group. These data corroborate results of a recently performed MCT study in patients with alcoholic and nonalcoholic cirrhosis giving evidence of a significant delay of MCT in patients with alcoholic cirrhosis (21). However, as gastric emptying was not measured in this study, the prolonged MCT values might have reflected simply a delay in gastric emptying. In our study abnormally slow MCT was detected in 14 of 37 alcoholics (37.8%), four of whom (28.6%) had delayed gastric emptying as well. Thus delayed gastric emptying may partly account for prolonged MCT in about a quarter of alcoholics with increased MCT times. Apart from results indicating a possible inhibition of rectosigmoid motility induced by acute ethanol administration (22), there is a lack of information on the effects of alcohol ingestion on colonic motor function. Our data do not reveal any difference of whole gut transit (WGT) time, largely reflecting colonic transit, in the alcoholics and the control subjects. As WGT was estimated with a relatively crude method--measuring the appearance time of the test meal in the stool this study may well have failed to detect subtle disorders of colonic motor function. In the alcoholics the presence of constipation was related to prolonged MCT as compared
922
to alcoholics without constipation and the control subjects. The causal factors of these observed gastric emptying and small intestinal transit disorders in chronic alcoholics remain to be elucidated. While the influence of factors related to the withdrawal phase cannot be excluded totally, our data do not suggest that the presence of hepatic cirrhosis or ascites has any effect on gastrointestinal transit times. Moreover neither abnormal gastric emptying nor abnormal MCT were related to autonomic or peripheral neuropathy. In fact, it has been demonstrated recently that esophageal motor dysfunction in chronic alcoholics is likewise independent of autonomic and peripheral neuropathy (13). This, however, does not rule out that alcohol-induced neuropathic damage might occur independently in different organs such as the enteric nervous system and the cardiovascular or the peripheral nerve system, and it should be stressed that in the present study autonomic function tests were limited to the cardiovascular system. Previous animal experimental and human studies have yielded strong evidence that alcohol is a muscle toxin that is toxic to striated muscle in a dose-dependent manner, producing a considerable frequency of cardiomyopathy and myopathy of skeletal muscle in chronic alcoholics (23, 24). It is thus tempting to speculate whether toxic damage of gastrointestinal smooth muscle is the underlying mechanism of gastrointestinal transit disorders in chronic alcoholism. The significant correlation of mean daily ethanol consumption and gastric emptying observed in this study may indicate that - - at least concerning gastric smooth muscle motor function m this ethanol-induced damage might be dosedependent. REFERENCES 1. Geokas MC, Lieber CS, French S, Halsted CH: Ethanol, the liver, and the gastrointestinal tract. Ann Intern Med 95:198211, 1981 2. Burbige EJ, Lewis DR, Halsted CH: Alcohol and the gastrointestinal tract. Med Clin North Am 68:77-89, 1984 3. Van Thiel DH, Lipsitz HD, Porter LE, Schade RR, Gottlieb GP, Graham TO: Gastrointestinal and hepatic manifestations of chronic alcoholism. Gastroenterology 81:594-615, 1981 4. Kjellen G, Tibbling L: Influence of body position, dry and water swallows, smoking, and alcohol on esophageal acid cleating. Scand J Gastroenterol 13:283-288, 1978 5. Kaufman SE, Kaye MD: Induction of gastro-oesophageal reflux by alcohol. Gut 19:336-338, 1978 Digestive Diseases and Sciences, Vol. 36, No. 7 (July 1991)
G A S T R O I N T E S T I N A L T R A N S I T IN C H R O N I C A L C O H O L I C S 6. Ewing DJ, Clarke BF: Diagnosis and management of diabetic autonomic neuropathy. Br Med J 285:916-918, 1982 7. Wegener M, B6rsch G, Schaffstein J, Luerweg C, Leverkus F: Gastrointestinal transit disorders in patients with insulintreated diabetes mellitus. Dig Dis 8:23-36, 1990 8. Wegener M, BOrsch G, Schaffstein J, Reuter C, Leverkus F: Frequency of idiopathic gastric stasis and intestinal transit disorders in essential dyspepsia. J Clin Gastroenterol 11:163-168, 1989 9. Collins PJ, Horowitz M, Cook DJ, Harding PE, Shearman DJC: Gastric emptying in normal subjects--a reproducible technique using a single scintillation camera and computer system. Gut 24:1117-1125, 1983 10. Mayer EM, Grabowski CJ, Fisher RS: Effects of graded doses of alcohol upon esophageal motor function. Gastroenterology 75:1133-1136, 1978 11. Keshavarzian A, Polepollo C, Iber FL, Durkin M, Morrissey M: Effect of acute and chronic ethanol on esophageal motility. Gastroenterology 95:A874, 1988 12. Silver LS, Worner TM, Korsten MA: Esophageal function in chronic alcoholics. Am J Gastroenterol 81:423-426, 1986 13. Keshavarzian A, Iber FL, Fergusson Y: Esophageal manometry and radionuclide emptying in chronic alcoholics. Gastroenterology 92:651-657, 1987 14. Barboriak JJ, Meade RC: Effect of alcohol on gastric emptying in man. Am J Clin Nutr 23:1151-1153, 1970
Digestive Diseases and Sciences, Vol. 36, No. 7 (July 1991)
15. Cooke AR: Ethanol and gastric function. Gastroenterology 62:501-502, 1972 16. Willson CA, Bushnell D, Keshavarzian A: The effect of acute and chronic ethanol administration on gastric emptying in cats. Dig Dis Sci 35:444-448, 1990 17. Hutson WR, Roehrkasse RL, Wald A: Influence of gender and menopause on gastric emptying and motility. Gastroenterology 96:11-17, 1989 18. Robles EA, Mezey E, Halsted CH, Schuster MM: Effect of ethanol on motility of the small intestine. Hopkins Med J 135:17-24, 1974 19. Ghimirie M, Morris AI, Hill D, Brownless SM, Stockdale HR, Patten MD: A mechanism for diarrhea in alcoholics. Gastroenterology 88:A1392, 1985 20. Keshavarzian A, Iber FL, Dangleis MD, Cornish R: Intestinal transit and lactose intolerance in chronic alcoholics. Am J Clin Nutr 44:70-76, 1986 21. Hiippe D, T6nissen R, Hofius M, Kuntz HD, May B: Influence of chronic alcoholism and liver cirrhosis on oro-cecal transit (H2 breath test). Z Gastroenterol 27:624-628, 1989 22. Berenson MM, Avner DL: Alcohol inhibition of rectosigmoid motility in humans. Digestion 22:210-215, 1981 23. Inoue F, Frank GB: Effects of ethyl alcohol on excitability and on neuromuscular transmission in frog skeletal muscle. Br J Pharmacol Chemother 30:186-193, 1967 24. Urbano-Marquez A, Estruch R, Navarro-Lopez F, Grau JM, Mont L, Rubin E: The effects of alcoholism on skeletal and cardiac muscle. N Engl J Med 320:409-415, 1989
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