- Email: [email protected]
Measurement of gastric bicarbonate secretion
2000
EDITORIALS
GASTROENTEROLOGY
2. Popper H, Schaffner F, eds. Nonsuppurative destructive chronic cholangitis and chronic hepatitis. Progress in liver disease. Vol. 3. New York: Grune & Stratton, 1970:336-54. 3. Ludwig J, Dickson ER, McDonald GSA. Staging of chronic nonsuppurative destructive cholangitis (syndrome of primary biliary cirrhosis). Virchows Arch [A] 1978;379:103-12, 4. Dickson ER, Fleming CR, Ludwig J. Primary biliary cirrhosis. In: Popper H, Schaffner F, eds. Progress in liver disease. Vol. 6. 6th ed. New York: Grune & Stratton, 1979:487-502. 5. MacSween RNM, Sumithran E. Histopathology biliary cirrhosis. Semin Liver Dis 1981;1:282-92.
of primary
6. Edmondson HA, Peters RL. Liver. In: Kissane JM, ed. Anderson’s pathology. Vol. 2. 8th ed. St. Louis; CV Mosby, 1985: 1096-212. 7. Scheuer PJ, ed. Biliary diseases and cholestasis. Liver biopsy
Vol.
88. No. 6
interpretation. 3rd ed. London: Baillierre, Tindall, and Casseil, 1980:47-59. 8. Nakanuma Y, Ohta G, Kobayashi K, Kato Y. Histological and histometric examination of the intrahepatic portal vein branches in primary biliary cirrhosis. Am J Gastroenterol 1982;77:405-13. 9. Wiesner RH, LaRusso NF, Ludwig J, Dickson ER. Comparison of the clinicopathologic features of primary sclerosing cholangitis and primary biliary cirrhosis. Gastroenterology 1985: 88:108-14. Address requests for reprints to: John Craig, M.D., University of Southern California Liver Unit, Ranch0 Los Amigos Hospital, 7705 Golondrinas Street-1200 Building, Downey, California 90242. 0 1985 by the American Gastroenterological Association
Measurement of Gastric Bicarbonate Secretion Recent work has demonstrated that there is a pH gradient at the surface af gastric and duodenal epithelium and that this gradient is generated by the secretion of HC03- from the surface epithelial cells into the visco-elastic mucus gel adherent to the Alkaline secretion together with the mucosa (l-4). surface mucus layer thus probably constitutes the first line of mucosal defence against luminal acid and pepsin (5). It is of considerable interest to study gastric alkaline secretion in humans but the determination of the secretion meets with several challenging difficulties. Some relate to our present understanding of mucosal defence. A low luminal pH together with bile or un-ionized aspirin overwhelms the alkalinity of the surface layer (I), resulting in acidification and damage to the lumen-facing cells. Passive diffusion or ultrafiltration of fluid containing HC03- from the interstitium across the damaged and leaky mucosa may be important in creating a suitable environment for mucosal repair (6) but must be distinguished from the metabolic-dependent alkaline secretion by intact epithelium (7). Further, possible deficits in alkaline secretion may be focal. In situ measurements of gastric surface pH using microelectrodes or other techniques would probably provide important information on this point. Demonstration of maintained alkalinity in the surface layer also excludes the possibility of “back diffusion” of H+ from the luminal solution across this layer into the mucosa (2). Luminal aspirin and several other mucosa-damaging agents induce apparent back diffusion (8) and findings that the alkalinity of the surface layer is overwhelmed by high luminal acidities alone (pH 1.4 in human mucosa in vitro) (9) suggest occurrence of back diffusion in apparently intact epithelium. These findings may, however, reflect diffusion of H+ along the barrel of the elec-
trode used to penetrate the mucus gel. There is thus a close quantitative correlation between the rate of HC03- secretion and H+ disappearance in the stomach of dogs, demonstrated in experiments where the HC03- stimulatory effect of luminal acid was considered (10) or HC03- secretion stimulated by 16,16dimethyl prostaglandin E, (11). An inherent problem in determining the alkaline secretion is that this secretion is usually masked by gastric acid secretion. Studies in animals indicate that neither histamine H, antagonists (5) nor omeprazole (12) affect gastric alkaline secretion. The Hz antagonist cimetidine has been used to inhibit H+ secretion in studies in humans where HC03- secretion was calculated from intragastric pH and PcoZ, using the Henderson-Hasselbalch equation (13-16). This technique relies upon the assumption that CO2 appearing intragastrically originates from the neutralization of secreted HC03- by H+. Diffusion of CO, out from or into the lumen is thus a possible source of error. The method has been tested by instilling exogenous HC03- into the gastric lumen (13,14,16) and, further, by converting secreted intragastric HC03into CO2 by addition of acid (14,16,17). Rapid perfusion (30 mlimin) of the stomach as used recently by Forssell and Olbe (16) should further decrease possible loss of COZ. Three laboratories (13,14,16) have demonstrated quantitative recovery of instilled HC03- and reported basal rates of gastric HC03- secretion in healthy volunteers of about 400 pmol/h. Interesting results from studies using another recently developed technique (18) are presented by Feldman and Barnett (19) in this issue of GASTROENTEROLOGY. Their methodology uses osmolality measurements and is based on the fact that reaction between HCO,- and H+ reduces the osmolality of
June
EDITORIALS
1985
the gastric juice. Consequently, a prerequisite for the method is that the permeability of the mucosa (and in particular the lumen-facing cells) to water is low. High permeability would result in movement of water along its chemical gradient from the lumen into the mucosa, increasing luminal osmolality and leading to an underestimation of HC03-- secretion. Further, hypotonicity of the gastric juice should arise only from reaction between secreted HCU, -and H’. The method was tested by demonstrating quantitative recoveries of instilled HC03- and fluid. The intriguing problem is that the rates of secretion reported by Feldman and Barnett (2300 2 SOCipmoli h in healthy volunteers) are considerably greater than those reported by laboratories calculating HC03secretion from pH and PCO~ measurements (-400 pmolih). One possible explanation is that hypotonicity of gastric juice arises from both reaction between secreted HC03- and
2001
stimulation by sham feeding (22) or infusion of bethanechol (18). The latter are inhibited by atropin. These effects as well as the inhibition of gastric alkaline secretion in humans by bile or aspirin (15) have also been demonstrated to occur in animals (5). The rate of gastric HC03- secretion in duodenal ulcer patients (479 ? 47 hmol/h, n = 13) is also not significantly different from that in healthy volunteers (428 ? 44 prpol/h, n = 20) when secretion is calculated from intragastric pH and PcoZ (Forssell, personal communication). Finally, direct measurements of pH at the mucosal surface (l-4,9) as well as recent model analyses (23) strongly suggest that neutralization of H+ diffusing from the lumen by HC03- diffusing from the epithelial surface occurs in a narrow zone within the surface mucus gel and not in the luminal bulk solution. Concentrations of HC03- in the nonparietal fluid as calculated by Feldman and Barnett (40-87 mEq/L) may thus be misleading. Immediate reaction between acid and high concentrations of HC03- (>23 mEq/L, assuming atmospheric pressure within the stomach and a solubility coefficient for CO, in the mucus gel of 0.03) would result in intragastric formation of CO;! gas bubbles. GUNNAR Department Biophysics Uppsala Uppsala,
FLEMSTRGM,
M.D.
of Physiology University
and
Biomedical
IMedical Center
Sweden
References 1. Ross IN. Bahari
HMM, Turnberg LA. The pH gradient across mucus adherent to rat fundic mucosa in vivo and the effect of 1981;81:713-8. potential damaging agents. Gastroenterology 2. FlemstrBm G, Kivilaakso E. Demonstration of a pH gradient at the luminal surface of rat duodenum in vivo and its dependence on mucosal alkaline secretion. Gastroenterology 1983; 84:787-94.
3. Takeuchi K, Magee D, Critchlow J. Matthews J, Silen W. Studies of the pH gradient and thickness of frog gastric mucus gel. Gastroenterology 1983:84:331-40. 4. Kivilaakso E. FlemstrBm G. Surface pH gradient in gastroduo1984:19(SuppJ 105):50denal mucosa. Stand J Gastroenterol 2.
5. Flemstrijm G. Turnberg LA. Gastroduodenal defence mechanisms. Clin Gastroenterol 1984;13:327-54. 6. Svanes K, Ito S, Takeuchi K. Silen W. Restitution of the surface epithelium of the in vitro frog gastric mucosa after damage with hyperosmolar sodium chloride: morphologic and physiologic characteristics. Gastroenterology 1982; 82:1409-26.
7. FlemstrBm G. Gastric secretion of bicarbonate. In: Johnson LR, Christensen J, Grossman MI, Jacobson ED, Schultz SG, eds. Physiology of the gastrointestinal tract. New York: Raven, 1981:603-16. 8. Davenport HW. Fluid produced by the gastric mucosa during damage by acetic and acetylsalicylic acid. Gastroenterology 1966:50:487-99.
2002
EDITORIALS
9. Bahari HMM, Ross IN, Turnberg LA. Demonstration of a pH gradient across the mucus layer on the surface of human gastric mucosa in vitro. Gut 1982;23:613-6. 10. Garner A, Hurst BC, Heylings JR, Flemstrom G. Role of gastroduodenal HCO,- transport in acid disposal and mucosal protection. In: Case RM, Garner A, Turnberg LA, Young JA, eds. Electrolyte and water transport across gastrointestinal epithelia. New York: Raven, X982239-52. 11. Miller TA, Kraemer BB, Henagan JM, Foucar CE. Topical 16,16-dimethyl prostaglandin Ez. Effects of gastric morphology, hydrogen ion loss, and bicarbonate secretion. Dig Dis Sci 1983;28:641-8. 12. Flemstrom G, Mattsson H. Effects of omeprazole on gastric and duodenal bicarbonate secretion. Stand J Gastroenterol (in press). 13. Rees WDW, Botham D, Turnberg LA. A demonstration of bicarbonate secretion by the normal human stomach in vivo. Dig Dis Sci 1982;27:961-6. 14. Johansson C, Aly A, Nilsson E, Flemstrom G. Stimulation of gastric bicarbonate secretion by EZ prostaglandins in man. Adv Prostaglandin Thromoboxane Leukotriene Res 1983; 12:395-401. 15. Rees WDW, Gibbons LC, Warhurst G, Turnberg LA. Studies of bicarbonate secretion by the normal human stomach in vivo: effect of aspirin, sodium taurocholate, and prostaglandin E,. In: Allen A, Flemstrom G, Garner A, Silen W, Turnberg LA, eds. Mechanisms of mucosal protection in the upper gastrointestinal tract. New York: Raven, 1984:119-27. 16. Forssell H, Olbe L. Continuous computerized determination of gastric bicarbonate secretion in man. Stand J Gastroenterol (in press).
GASTROENTEROLOGY Vol. 88, No. 6
17. Garner
18.
19.
20.
21.
22.
23.
A, Flemstrom G. Gastric HC03- secretion in the guinea pig. Am J Physiol 1978;234:E535-45. Feldman M. Gastric bicarbonate secretion in humans. Effect of pentagastrin, bethanechol, and 11,16,16-trimethyl prostaglandin E,. J Clin Invest 1983;72:295-303. Feldman M, Barnett CC. Gastric bicarbonate secretion in patients with duodenal ulcer. Gastroenterology 1985;88:12058. Rehm WS, Butler CF, Spangler SG, Sanders SS. A model to explain uphill water transport in the mammalian stomach. J Theor Biol 1970;27:433-53. Makhlouf GM. Electrolyte composition of gastric secretion. In: Johnson LR, Christensen J, Grossman MI, Jacobson ED, Schultz SG, eds. Physiology of the gastrointestinal tract. New York: Raven, 1981:551-66. Forssell H, Olbe L. Continuous measurement of gastric bicarbonate secretion in man under basal conditions and after sham feeding (abstr). Stand J Gastroenterol 1985;2O(Suppl 110):55. Engel E, Peskoff A, Kauffman GL, Grossman MI. Analysis of hydrogen ion concentration in the gastric gel mucus layer. Am J Physiol 1984;247:G321-38.
Address requests for reprints to: Gunnar Flemstrom, M.D., Department of Physiology and Medical Biophysics, Uppsala University Biomedical Center, P.O. Box 572, S-751 23 Uppsala, Sweden. 0 1985 by the American Gastroenterological Association
EDITORIALS
GASTROENTEROLOGY
2. Popper H, Schaffner F, eds. Nonsuppurative destructive chronic cholangitis and chronic hepatitis. Progress in liver disease. Vol. 3. New York: Grune & Stratton, 1970:336-54. 3. Ludwig J, Dickson ER, McDonald GSA. Staging of chronic nonsuppurative destructive cholangitis (syndrome of primary biliary cirrhosis). Virchows Arch [A] 1978;379:103-12, 4. Dickson ER, Fleming CR, Ludwig J. Primary biliary cirrhosis. In: Popper H, Schaffner F, eds. Progress in liver disease. Vol. 6. 6th ed. New York: Grune & Stratton, 1979:487-502. 5. MacSween RNM, Sumithran E. Histopathology biliary cirrhosis. Semin Liver Dis 1981;1:282-92.
of primary
6. Edmondson HA, Peters RL. Liver. In: Kissane JM, ed. Anderson’s pathology. Vol. 2. 8th ed. St. Louis; CV Mosby, 1985: 1096-212. 7. Scheuer PJ, ed. Biliary diseases and cholestasis. Liver biopsy
Vol.
88. No. 6
interpretation. 3rd ed. London: Baillierre, Tindall, and Casseil, 1980:47-59. 8. Nakanuma Y, Ohta G, Kobayashi K, Kato Y. Histological and histometric examination of the intrahepatic portal vein branches in primary biliary cirrhosis. Am J Gastroenterol 1982;77:405-13. 9. Wiesner RH, LaRusso NF, Ludwig J, Dickson ER. Comparison of the clinicopathologic features of primary sclerosing cholangitis and primary biliary cirrhosis. Gastroenterology 1985: 88:108-14. Address requests for reprints to: John Craig, M.D., University of Southern California Liver Unit, Ranch0 Los Amigos Hospital, 7705 Golondrinas Street-1200 Building, Downey, California 90242. 0 1985 by the American Gastroenterological Association
Measurement of Gastric Bicarbonate Secretion Recent work has demonstrated that there is a pH gradient at the surface af gastric and duodenal epithelium and that this gradient is generated by the secretion of HC03- from the surface epithelial cells into the visco-elastic mucus gel adherent to the Alkaline secretion together with the mucosa (l-4). surface mucus layer thus probably constitutes the first line of mucosal defence against luminal acid and pepsin (5). It is of considerable interest to study gastric alkaline secretion in humans but the determination of the secretion meets with several challenging difficulties. Some relate to our present understanding of mucosal defence. A low luminal pH together with bile or un-ionized aspirin overwhelms the alkalinity of the surface layer (I), resulting in acidification and damage to the lumen-facing cells. Passive diffusion or ultrafiltration of fluid containing HC03- from the interstitium across the damaged and leaky mucosa may be important in creating a suitable environment for mucosal repair (6) but must be distinguished from the metabolic-dependent alkaline secretion by intact epithelium (7). Further, possible deficits in alkaline secretion may be focal. In situ measurements of gastric surface pH using microelectrodes or other techniques would probably provide important information on this point. Demonstration of maintained alkalinity in the surface layer also excludes the possibility of “back diffusion” of H+ from the luminal solution across this layer into the mucosa (2). Luminal aspirin and several other mucosa-damaging agents induce apparent back diffusion (8) and findings that the alkalinity of the surface layer is overwhelmed by high luminal acidities alone (pH 1.4 in human mucosa in vitro) (9) suggest occurrence of back diffusion in apparently intact epithelium. These findings may, however, reflect diffusion of H+ along the barrel of the elec-
trode used to penetrate the mucus gel. There is thus a close quantitative correlation between the rate of HC03- secretion and H+ disappearance in the stomach of dogs, demonstrated in experiments where the HC03- stimulatory effect of luminal acid was considered (10) or HC03- secretion stimulated by 16,16dimethyl prostaglandin E, (11). An inherent problem in determining the alkaline secretion is that this secretion is usually masked by gastric acid secretion. Studies in animals indicate that neither histamine H, antagonists (5) nor omeprazole (12) affect gastric alkaline secretion. The Hz antagonist cimetidine has been used to inhibit H+ secretion in studies in humans where HC03- secretion was calculated from intragastric pH and PcoZ, using the Henderson-Hasselbalch equation (13-16). This technique relies upon the assumption that CO2 appearing intragastrically originates from the neutralization of secreted HC03- by H+. Diffusion of CO, out from or into the lumen is thus a possible source of error. The method has been tested by instilling exogenous HC03- into the gastric lumen (13,14,16) and, further, by converting secreted intragastric HC03into CO2 by addition of acid (14,16,17). Rapid perfusion (30 mlimin) of the stomach as used recently by Forssell and Olbe (16) should further decrease possible loss of COZ. Three laboratories (13,14,16) have demonstrated quantitative recovery of instilled HC03- and reported basal rates of gastric HC03- secretion in healthy volunteers of about 400 pmol/h. Interesting results from studies using another recently developed technique (18) are presented by Feldman and Barnett (19) in this issue of GASTROENTEROLOGY. Their methodology uses osmolality measurements and is based on the fact that reaction between HCO,- and H+ reduces the osmolality of
June
EDITORIALS
1985
the gastric juice. Consequently, a prerequisite for the method is that the permeability of the mucosa (and in particular the lumen-facing cells) to water is low. High permeability would result in movement of water along its chemical gradient from the lumen into the mucosa, increasing luminal osmolality and leading to an underestimation of HC03-- secretion. Further, hypotonicity of the gastric juice should arise only from reaction between secreted HCU, -and H’. The method was tested by demonstrating quantitative recoveries of instilled HC03- and fluid. The intriguing problem is that the rates of secretion reported by Feldman and Barnett (2300 2 SOCipmoli h in healthy volunteers) are considerably greater than those reported by laboratories calculating HC03secretion from pH and PCO~ measurements (-400 pmolih). One possible explanation is that hypotonicity of gastric juice arises from both reaction between secreted HC03- and
2001
stimulation by sham feeding (22) or infusion of bethanechol (18). The latter are inhibited by atropin. These effects as well as the inhibition of gastric alkaline secretion in humans by bile or aspirin (15) have also been demonstrated to occur in animals (5). The rate of gastric HC03- secretion in duodenal ulcer patients (479 ? 47 hmol/h, n = 13) is also not significantly different from that in healthy volunteers (428 ? 44 prpol/h, n = 20) when secretion is calculated from intragastric pH and PcoZ (Forssell, personal communication). Finally, direct measurements of pH at the mucosal surface (l-4,9) as well as recent model analyses (23) strongly suggest that neutralization of H+ diffusing from the lumen by HC03- diffusing from the epithelial surface occurs in a narrow zone within the surface mucus gel and not in the luminal bulk solution. Concentrations of HC03- in the nonparietal fluid as calculated by Feldman and Barnett (40-87 mEq/L) may thus be misleading. Immediate reaction between acid and high concentrations of HC03- (>23 mEq/L, assuming atmospheric pressure within the stomach and a solubility coefficient for CO, in the mucus gel of 0.03) would result in intragastric formation of CO;! gas bubbles. GUNNAR Department Biophysics Uppsala Uppsala,
FLEMSTRGM,
M.D.
of Physiology University
and
Biomedical
IMedical Center
Sweden
References 1. Ross IN. Bahari
HMM, Turnberg LA. The pH gradient across mucus adherent to rat fundic mucosa in vivo and the effect of 1981;81:713-8. potential damaging agents. Gastroenterology 2. FlemstrBm G, Kivilaakso E. Demonstration of a pH gradient at the luminal surface of rat duodenum in vivo and its dependence on mucosal alkaline secretion. Gastroenterology 1983; 84:787-94.
3. Takeuchi K, Magee D, Critchlow J. Matthews J, Silen W. Studies of the pH gradient and thickness of frog gastric mucus gel. Gastroenterology 1983:84:331-40. 4. Kivilaakso E. FlemstrBm G. Surface pH gradient in gastroduo1984:19(SuppJ 105):50denal mucosa. Stand J Gastroenterol 2.
5. Flemstrijm G. Turnberg LA. Gastroduodenal defence mechanisms. Clin Gastroenterol 1984;13:327-54. 6. Svanes K, Ito S, Takeuchi K. Silen W. Restitution of the surface epithelium of the in vitro frog gastric mucosa after damage with hyperosmolar sodium chloride: morphologic and physiologic characteristics. Gastroenterology 1982; 82:1409-26.
7. FlemstrBm G. Gastric secretion of bicarbonate. In: Johnson LR, Christensen J, Grossman MI, Jacobson ED, Schultz SG, eds. Physiology of the gastrointestinal tract. New York: Raven, 1981:603-16. 8. Davenport HW. Fluid produced by the gastric mucosa during damage by acetic and acetylsalicylic acid. Gastroenterology 1966:50:487-99.
2002
EDITORIALS
9. Bahari HMM, Ross IN, Turnberg LA. Demonstration of a pH gradient across the mucus layer on the surface of human gastric mucosa in vitro. Gut 1982;23:613-6. 10. Garner A, Hurst BC, Heylings JR, Flemstrom G. Role of gastroduodenal HCO,- transport in acid disposal and mucosal protection. In: Case RM, Garner A, Turnberg LA, Young JA, eds. Electrolyte and water transport across gastrointestinal epithelia. New York: Raven, X982239-52. 11. Miller TA, Kraemer BB, Henagan JM, Foucar CE. Topical 16,16-dimethyl prostaglandin Ez. Effects of gastric morphology, hydrogen ion loss, and bicarbonate secretion. Dig Dis Sci 1983;28:641-8. 12. Flemstrom G, Mattsson H. Effects of omeprazole on gastric and duodenal bicarbonate secretion. Stand J Gastroenterol (in press). 13. Rees WDW, Botham D, Turnberg LA. A demonstration of bicarbonate secretion by the normal human stomach in vivo. Dig Dis Sci 1982;27:961-6. 14. Johansson C, Aly A, Nilsson E, Flemstrom G. Stimulation of gastric bicarbonate secretion by EZ prostaglandins in man. Adv Prostaglandin Thromoboxane Leukotriene Res 1983; 12:395-401. 15. Rees WDW, Gibbons LC, Warhurst G, Turnberg LA. Studies of bicarbonate secretion by the normal human stomach in vivo: effect of aspirin, sodium taurocholate, and prostaglandin E,. In: Allen A, Flemstrom G, Garner A, Silen W, Turnberg LA, eds. Mechanisms of mucosal protection in the upper gastrointestinal tract. New York: Raven, 1984:119-27. 16. Forssell H, Olbe L. Continuous computerized determination of gastric bicarbonate secretion in man. Stand J Gastroenterol (in press).
GASTROENTEROLOGY Vol. 88, No. 6
17. Garner
18.
19.
20.
21.
22.
23.
A, Flemstrom G. Gastric HC03- secretion in the guinea pig. Am J Physiol 1978;234:E535-45. Feldman M. Gastric bicarbonate secretion in humans. Effect of pentagastrin, bethanechol, and 11,16,16-trimethyl prostaglandin E,. J Clin Invest 1983;72:295-303. Feldman M, Barnett CC. Gastric bicarbonate secretion in patients with duodenal ulcer. Gastroenterology 1985;88:12058. Rehm WS, Butler CF, Spangler SG, Sanders SS. A model to explain uphill water transport in the mammalian stomach. J Theor Biol 1970;27:433-53. Makhlouf GM. Electrolyte composition of gastric secretion. In: Johnson LR, Christensen J, Grossman MI, Jacobson ED, Schultz SG, eds. Physiology of the gastrointestinal tract. New York: Raven, 1981:551-66. Forssell H, Olbe L. Continuous measurement of gastric bicarbonate secretion in man under basal conditions and after sham feeding (abstr). Stand J Gastroenterol 1985;2O(Suppl 110):55. Engel E, Peskoff A, Kauffman GL, Grossman MI. Analysis of hydrogen ion concentration in the gastric gel mucus layer. Am J Physiol 1984;247:G321-38.
Address requests for reprints to: Gunnar Flemstrom, M.D., Department of Physiology and Medical Biophysics, Uppsala University Biomedical Center, P.O. Box 572, S-751 23 Uppsala, Sweden. 0 1985 by the American Gastroenterological Association