1996
CORRESPONDENCE
the analysis performed on the data, and their subsequent conclusions. To determine postprandial gallbladder contractility, gallbladder volumes must be related to the basal preprandial volumes, a standard and widely recognized technique.*s3 In the current study it appears that the application of this technique was incorrect, because postprandial gallbladder volumes in the erythromycin group were compared with preprandial volumes in the placebo group, rather than, as would be appropriate, with the preprandial volumes after erythromycin administration. As the data show an effect of erythromycin on fasting gallbladder volumes, a parallel shift of the curves can be seen in Figure 2A in the article, falsely suggesting a profound effect of erythromycin on postprandial gallbladder motility. After correction for this parallel shift by normalizing these curves to lOO%, it is evident that erythromycin has no effect on postprandial gallbladder motility in healthy humans and only a minor effect in patients with gallstones and those with previous percutaneous cholecystolithotomy. Decreases in gallbladder motility may well be important in the etiology of recurrent cholelithiasis3 but because erythromycin appears to have only a minimal effect on postprandial gallbladder contractility, it may not be useful in this condition. It is also well recognized that gastric emptying rates influence gallbladder motility. *.4.5Erythromycin has a profound effect on gastric motility, markedly accelerating gastric emptying rates of liquid and solid meals.6 It is therefore possible that any effect of erythromycin on gallbladder contractility is secondary to the marked acceleration of gastric emptying following erythromycin administration. Catnach et al. argue that this is unlikely because there was no alteration in the timing of gallbladder emptying or in the onset of gallbladder refilling. However, in their Figure 2 the timing of gallbladder refilling cannot be clearly defined because of the short observation period (40 minutes). We consider simultaneous measurements of gastric emptying and gallbladder contractility to be necessary to determine whether prokinetic drugs have a direct effect on gallbladder motility.Z.4 We think these issues are important when assessing the results reported by Catnach et al. and that further investigations are necessary to determine the effect of erythromycin on gallbladder motility. For the time being, it is in our opinion unjustified to assume a direct effect of erythromycin on postprandial gallbladder motility. MICHAEL FRIED, M.D. FLORIAN FROEHLICH, M.D. JOiiL THORENS, M.D. ANDRB BLUM, M.D. ROB FRASER, M.D. JEAN-JACQUES GONVERS, M.D.
Division de Gastroente’rologie PMU/CHUV Policlinique me’dicale universitaire Cdsar-Roux 19 CH-1005 Lausanne, Switzerland Catnach SM, Fairclough PD, Trembath RC, O’Donnell LJD, McLean AM, Law PA, Wickham JEA. Effect of oral erythromytin on gallbladder motility in normal subjects and subjects with gallstones. Gastroenterology 1992;102:2071-2076. Lawson M, Everson GT, Klingensmith W, Kern F. Coordination of gastric and gallbladder emptying after ingestion of a regular meal. Gastroenterology 1983;85:866-870. Spengler U, Sackmann M, Sauerbruch T, Ho11 J, Paumgartner G. Gallbladder motility before and after extracorporeal shockwave lithotripsy. Gastroenterology 1989;96:860-863. Baxter JN, Grime JS, Critchley M, Jenkins SA, Shields R. Relationship between gastric emptying of a solid meal and emptying of the gallbladder before and after vagotomy. Gut 1987;28:855-863.
GASTROENTEROLOGY Vol. 103, No. 6
5. Fried M, Mayer EA, Jansen JBMJ, Lamers CBHW, Taylor IL, Bloom SR, Meyer JH. Temporal relationships of cholecystokinin release, pancreatobiliary secretion, and gastric emptying of a mixed meal. Gastroenterology 1988;95:1344-1350. 6. Janssens J, Peeters TL, Vantrapppen G, Tack J, Urbain JL, De Roo M, Muls E, Bouillos R. Improvement of gastric emptying in diabetic gastroparesis by erythromycin. N Engl J Med 1990;322:1028-1031. Reply. We thank Dr. Fried et al. for their interest in our work. However, we believe that they have missed several important points. It is not disputed that the major effect of erythromycin on the gallbladder is a reduction of fasting volume; indeed, the figures were drawn precisely to emphasize this point. There is also an effect on postprandial gallbladder contraction because the emptying curves are in fact not quite parallel, as shown by the differences in the rate constant of gallbladder emptying. In addition, the postprandial residual volume-arguably the most important determinant of gallbladder stasis-is substantially reduced in all groups. An effect of erythromycin on gallbladder motility in subjects with gallstones is undoubted because erythromycin caused 7 of 8 such noncontracting gallbladders to empty. The effect of erythromycin on gastric emptying of nutrients can hardly account for gallbladder contraction in the fasting state, although we accept that postprandial gallbladder contraction could be related to its effect on duodenal nutrient delivery, as discussed in our paper. SUSAN M. CATNACH, M.D. PETER D. FAIRCLOUGH. M.D., F.R.C.P.
Gastroenteralogy Department St. Bartholomew’s Hospital West Smithfield, London EClA 7BE, England
Atria1 Natriuretic Cirrhosis
Factor in Experimental
Dear Sir: Morgan et al.’ report on plasma atria1 natriuretic factor (ANF) concentrations, atria1 ANF messenger RNA (mRNA) levels, and binding of ANF to glomerular receptors in cirrhotic rats without ascites. They report increased atria1 ANF mRNA levels and increased glomerular receptor density in cirrhotic animals and note that these changes are in the same direction as those reported in cirrhosis with ascites. They conclude that progressive alterations in renal ANF-receptor density or function in cirrhosis could contribute to sodium retention. Although this conclusion may be correct, the interpretation of their study is hindered by uncertainty as to whether the cirrhotic animals were retaining sodium at the time of investigation. The presence or absence of visible ascites may not be a good indicator of the current state of sodium handling in the cirrhotic rat. The presence of ascites clearly implies that there has been a period of sodium retention but is entirely compatible with a positive, neutral, or negative sodium balance at the time ascites is observed. Similarly, an animal without ascites may be in any one of these states. A major factor influencing the state of sodium balance and the formation (or resolution) of ascites is the sodium content of the diet,’ a matter not commented on by Morgan et al.’ As part of an experimental protocol designed to investigate aspects of fluid volume homeostasis in the rat with carbon tetrachloride-induced cirrhosis, we assessed sodium handling in vivo in 25 rats with histologically proven cirrhosis and 25 age-matched controls while rats were on a diet containing 0.21% sodium. Five milliliters of a solution containing 2 mmol of sodium chloride was administered by gavage. 3*4Cumulative urine sodium excretion (percent of sodium load) was markedly reduced in the 25 cirrhotic
December
1992
CORRESPONDENCE
rats 4.5% f 0.74% (mean + SEM) after 4 hours compared with the 25 controls (40.8%+ 4.2%).When the same rats were examined for the presence of ascites at the time of opening the abdomen, 7-23 days later, a large amount of ascites was visible in 13 and a small amount in 8, and none was visible in 4 (although bowel edema was present). Impaired sodium excretion had been observed in all of the cirrhotic animals. We suggest that, in experiments dealing with aspects of sodium homeostasis in cirrhotic rats, an essential first step should be the administration of a standard sodium challenge in vivo to define accurately the sodium-handling status of the experimental animal. MARIOS Z. PANOS East Birmingham Hospital University of Birmingham Birmingham B9 5ST, England CHRISTOPHERD. ROGER
GOVE
WILLIAMS
Institute of Liver Studies King’s College Hospital London SE 5, England
1997
JOHN D. FIRTH Nuffeld Department of Clinical Medicine John Radcliffe Hospital Oxford, England ANTHONY E. G. RAINE Department of Nephrology Royal Hospital ofSt. Bartholomew London ECl, England
1. Morgan TR, Morgan K, Jonas GM, Thillainadarajah I. Atria1 natriuretic factor in experimental cirrhosis. Gastroenterology 1992;102:1356-1362. 2. Sherlock S. Ascites. In: Diseases of the liver and biliary system. 7th ed. New York: Blackwell, 1985:117-134. 3. Firth JD, Gove CD, Panos MZ, Raine AEG, Williams R, Ledingham JGG. Sodium handling in the isolated perfused kidney of the cirrhotic rat. Clin Sci 1989;79:67-71. 4. Panos MZ, Gove CD, Firth JD, Raine AEG, Ledingham JGG, Westaby D, Williams R. Resistance to the natriuretic action of atria1 natriuretic peptide on the isolated kidney of rats with experimental cirrhosis. Clin Sci 1990;79:67-71.
CORRESPONDENCE
the analysis performed on the data, and their subsequent conclusions. To determine postprandial gallbladder contractility, gallbladder volumes must be related to the basal preprandial volumes, a standard and widely recognized technique.*s3 In the current study it appears that the application of this technique was incorrect, because postprandial gallbladder volumes in the erythromycin group were compared with preprandial volumes in the placebo group, rather than, as would be appropriate, with the preprandial volumes after erythromycin administration. As the data show an effect of erythromycin on fasting gallbladder volumes, a parallel shift of the curves can be seen in Figure 2A in the article, falsely suggesting a profound effect of erythromycin on postprandial gallbladder motility. After correction for this parallel shift by normalizing these curves to lOO%, it is evident that erythromycin has no effect on postprandial gallbladder motility in healthy humans and only a minor effect in patients with gallstones and those with previous percutaneous cholecystolithotomy. Decreases in gallbladder motility may well be important in the etiology of recurrent cholelithiasis3 but because erythromycin appears to have only a minimal effect on postprandial gallbladder contractility, it may not be useful in this condition. It is also well recognized that gastric emptying rates influence gallbladder motility. *.4.5Erythromycin has a profound effect on gastric motility, markedly accelerating gastric emptying rates of liquid and solid meals.6 It is therefore possible that any effect of erythromycin on gallbladder contractility is secondary to the marked acceleration of gastric emptying following erythromycin administration. Catnach et al. argue that this is unlikely because there was no alteration in the timing of gallbladder emptying or in the onset of gallbladder refilling. However, in their Figure 2 the timing of gallbladder refilling cannot be clearly defined because of the short observation period (40 minutes). We consider simultaneous measurements of gastric emptying and gallbladder contractility to be necessary to determine whether prokinetic drugs have a direct effect on gallbladder motility.Z.4 We think these issues are important when assessing the results reported by Catnach et al. and that further investigations are necessary to determine the effect of erythromycin on gallbladder motility. For the time being, it is in our opinion unjustified to assume a direct effect of erythromycin on postprandial gallbladder motility. MICHAEL FRIED, M.D. FLORIAN FROEHLICH, M.D. JOiiL THORENS, M.D. ANDRB BLUM, M.D. ROB FRASER, M.D. JEAN-JACQUES GONVERS, M.D.
Division de Gastroente’rologie PMU/CHUV Policlinique me’dicale universitaire Cdsar-Roux 19 CH-1005 Lausanne, Switzerland Catnach SM, Fairclough PD, Trembath RC, O’Donnell LJD, McLean AM, Law PA, Wickham JEA. Effect of oral erythromytin on gallbladder motility in normal subjects and subjects with gallstones. Gastroenterology 1992;102:2071-2076. Lawson M, Everson GT, Klingensmith W, Kern F. Coordination of gastric and gallbladder emptying after ingestion of a regular meal. Gastroenterology 1983;85:866-870. Spengler U, Sackmann M, Sauerbruch T, Ho11 J, Paumgartner G. Gallbladder motility before and after extracorporeal shockwave lithotripsy. Gastroenterology 1989;96:860-863. Baxter JN, Grime JS, Critchley M, Jenkins SA, Shields R. Relationship between gastric emptying of a solid meal and emptying of the gallbladder before and after vagotomy. Gut 1987;28:855-863.
GASTROENTEROLOGY Vol. 103, No. 6
5. Fried M, Mayer EA, Jansen JBMJ, Lamers CBHW, Taylor IL, Bloom SR, Meyer JH. Temporal relationships of cholecystokinin release, pancreatobiliary secretion, and gastric emptying of a mixed meal. Gastroenterology 1988;95:1344-1350. 6. Janssens J, Peeters TL, Vantrapppen G, Tack J, Urbain JL, De Roo M, Muls E, Bouillos R. Improvement of gastric emptying in diabetic gastroparesis by erythromycin. N Engl J Med 1990;322:1028-1031. Reply. We thank Dr. Fried et al. for their interest in our work. However, we believe that they have missed several important points. It is not disputed that the major effect of erythromycin on the gallbladder is a reduction of fasting volume; indeed, the figures were drawn precisely to emphasize this point. There is also an effect on postprandial gallbladder contraction because the emptying curves are in fact not quite parallel, as shown by the differences in the rate constant of gallbladder emptying. In addition, the postprandial residual volume-arguably the most important determinant of gallbladder stasis-is substantially reduced in all groups. An effect of erythromycin on gallbladder motility in subjects with gallstones is undoubted because erythromycin caused 7 of 8 such noncontracting gallbladders to empty. The effect of erythromycin on gastric emptying of nutrients can hardly account for gallbladder contraction in the fasting state, although we accept that postprandial gallbladder contraction could be related to its effect on duodenal nutrient delivery, as discussed in our paper. SUSAN M. CATNACH, M.D. PETER D. FAIRCLOUGH. M.D., F.R.C.P.
Gastroenteralogy Department St. Bartholomew’s Hospital West Smithfield, London EClA 7BE, England
Atria1 Natriuretic Cirrhosis
Factor in Experimental
Dear Sir: Morgan et al.’ report on plasma atria1 natriuretic factor (ANF) concentrations, atria1 ANF messenger RNA (mRNA) levels, and binding of ANF to glomerular receptors in cirrhotic rats without ascites. They report increased atria1 ANF mRNA levels and increased glomerular receptor density in cirrhotic animals and note that these changes are in the same direction as those reported in cirrhosis with ascites. They conclude that progressive alterations in renal ANF-receptor density or function in cirrhosis could contribute to sodium retention. Although this conclusion may be correct, the interpretation of their study is hindered by uncertainty as to whether the cirrhotic animals were retaining sodium at the time of investigation. The presence or absence of visible ascites may not be a good indicator of the current state of sodium handling in the cirrhotic rat. The presence of ascites clearly implies that there has been a period of sodium retention but is entirely compatible with a positive, neutral, or negative sodium balance at the time ascites is observed. Similarly, an animal without ascites may be in any one of these states. A major factor influencing the state of sodium balance and the formation (or resolution) of ascites is the sodium content of the diet,’ a matter not commented on by Morgan et al.’ As part of an experimental protocol designed to investigate aspects of fluid volume homeostasis in the rat with carbon tetrachloride-induced cirrhosis, we assessed sodium handling in vivo in 25 rats with histologically proven cirrhosis and 25 age-matched controls while rats were on a diet containing 0.21% sodium. Five milliliters of a solution containing 2 mmol of sodium chloride was administered by gavage. 3*4Cumulative urine sodium excretion (percent of sodium load) was markedly reduced in the 25 cirrhotic
December
1992
CORRESPONDENCE
rats 4.5% f 0.74% (mean + SEM) after 4 hours compared with the 25 controls (40.8%+ 4.2%).When the same rats were examined for the presence of ascites at the time of opening the abdomen, 7-23 days later, a large amount of ascites was visible in 13 and a small amount in 8, and none was visible in 4 (although bowel edema was present). Impaired sodium excretion had been observed in all of the cirrhotic animals. We suggest that, in experiments dealing with aspects of sodium homeostasis in cirrhotic rats, an essential first step should be the administration of a standard sodium challenge in vivo to define accurately the sodium-handling status of the experimental animal. MARIOS Z. PANOS East Birmingham Hospital University of Birmingham Birmingham B9 5ST, England CHRISTOPHERD. ROGER
GOVE
WILLIAMS
Institute of Liver Studies King’s College Hospital London SE 5, England
1997
JOHN D. FIRTH Nuffeld Department of Clinical Medicine John Radcliffe Hospital Oxford, England ANTHONY E. G. RAINE Department of Nephrology Royal Hospital ofSt. Bartholomew London ECl, England
1. Morgan TR, Morgan K, Jonas GM, Thillainadarajah I. Atria1 natriuretic factor in experimental cirrhosis. Gastroenterology 1992;102:1356-1362. 2. Sherlock S. Ascites. In: Diseases of the liver and biliary system. 7th ed. New York: Blackwell, 1985:117-134. 3. Firth JD, Gove CD, Panos MZ, Raine AEG, Williams R, Ledingham JGG. Sodium handling in the isolated perfused kidney of the cirrhotic rat. Clin Sci 1989;79:67-71. 4. Panos MZ, Gove CD, Firth JD, Raine AEG, Ledingham JGG, Westaby D, Williams R. Resistance to the natriuretic action of atria1 natriuretic peptide on the isolated kidney of rats with experimental cirrhosis. Clin Sci 1990;79:67-71.
