LETTERS TO THE EDITOR
FLEXIBLE SIGMOIDOSCOPY To The Editor: The paper by Dr. Winawer and his associates (24:277-281) on the use of flexible sigmoidoscopy echoes our sentiments after using this instrument in more than one hundred patients during the past eight months. We, too, perform the examination as an outpatient procedure, usually as a prelude to a barium enema on the same morning. However, we always use the left lateral position since this is more readily accepted by the patient and is less "strenuous," especially in the elderly. Furthermore, we reach a distance of 65 cm (the full length of the instrument) in well over 90% of our patients and well within a period of ten minutes. As " s p a s m " is the usual reason one fails to reach this level we premedicate our patients with 5-10 mg of intravenous diazepam (Valium). Perhaps, this is why so many of our patients "recommend" us to their friends! LEE SATALINE, MD Chief, G.1. Section TERRI
GOFFRED
GI Assistant Bradley Memorial Hospital and Health Center Southington, Connecticut
PHYSIOLOGICAL BASIS OF ISCHEMIC ENTEROPATHY To The Editor: In recent years there has been an increased interest in the specific susceptibility of the intestinal mucosa to low flow states (1-21). In this letter I propose a theory relating this phenomenon to some specific aspects of intestinal physiology. Several years ago we demonstrated that changes induced by circulatory insufficiency in the small bowel mucosa of the dog may include an increased vulnerability to the digestive action of trypsin and chymotrypsin: hemorrhagic necrosis of the mucosa induced by shock is minimized by previous inhibition of trypsin and chymotx:ypsin in the intestinal lumen (7) or by previous ligation of the pancreatic ducts (8). It was postulated that such changes were
somehow related to the disappearance of the mucus coat covering the lining epithelium observed in the early stages of severe hypotension (9). Numerous studies, carried out in four animal species, have since confirmed these original findings (10-20). Although these studies provide evidence that pancreatic proteases play an important role in the advanced phase of ischemia, they failed to define the relative role of different pancreatic enzymes in the early as well as advanced phases of ischemia. Recent experiments in rats have helped us to better u n d e r s t a n d the role of pancreatic endopeptidases and bile in the pathogenesis of the small bowel mucosal lesion during ischemia (21, 22). The loss of total brush border proteins and activities of sucrase, trehalase, glutamyltransferase (GGT Pase) and leucylnaphtylamidase (LNA ase) observed after 45 min of ischemia is substantially reduced by previous lavage of the lumen by saline perfusion, but it is not influenced by prior inhibition of luminal trypsin and chymotrypsin with Trasylol (21). Thus factors within the lumen other than trypsin are partially responsible for the loss of brush border proteins which occurs after short-term occlusion of the mesenteric artery. The effect of elastase was estimated by either adding, before ischemia, a physiological amount of the enzym e to the lumen after complete intestinal perfusion (21) or by previous inhibition of elastase with turkey ovomucoid (22): while the former treatment enhances the loss of brush border proteins, the latter substantially reduces it. The role of bile salts was investigated by adding cuemid to the lumen before ischemia: this partially protects the brush border from the effects of 45 min ischemia (22). When mesenteric artery occlusion was prolonged to 100 min, previous selective inhibition of luminal trypsin and chymotrypsin with Trasylol minimized its effects on loss of mucosal weight, DNA, and proteins (21). Our observations following 45 rain ischemia are consistent with recent physiological experiments by Alpers and Tedesco (23) in rats and Maestracci (24) in man, showing that pancreatic elastase plays a natural role in stripping glycoproteins from the brush border. A similar role for bile salts was suggested by Vasseur et al (25). In conclusion, our biochemical data, consistent with the morphological picture, suggest the following theory:
Digestive Diseases and Sciences, Vol. 24, No. 11 (November 1979) 0163-2116/79/1100-0891503.00/1 9 1979 Digestive Disease Systems, Inc.
891
L E T T E R S TO T H E EDITOR The physiological loss of brush border glycoproteins, produced by the action of pancreatic elastase a n d bile s a l t s , s u d d e n l y b e c o m e s a p a t h o l o g i c a l p h e n o m e n o n if i m p a i r m e n t o f m e s e n t e r i c b l o o d flow p r e v e n t s t h e s t e a d y r e g e n e r a t i o n o f t h e s e front-line constituents of the small bowel mucosa. I n t h e initial p h a s e o f i s c h e m i a , t h e s e f a c t o r s w i t h i n t h e i n t e s t i n a l l u m e n c o n t r i b u t e s u b s t a n t i a l l y to t h e loss of brush border proteins. After the disa p p e a r a n c e o f t h e b r u s h b o r d e r , in t h e a d v a n c e d phase of ischemia, the protection by trypsin-resist a n t g l y c o p r o t e i n s is l o s t ; h e n c e t h e u n d e r l y i n g structures are accessible to the digestive action of t h e p a n c r e a t i c e n d o p e p t i d a s e s p r e s e n t a l o n g t h e intestinal wall and lumen. GUSTAVO BOUNOUS, M D C e n t r e H o s p i t a l i e r Universitaire Sherbrooke, QuObec, C a n a d a REFERENCES
1. Penner A, Bernhein AI: Acute postoperative enterocolitis. A study on the pathologic nature of shock. Arch Patho127:966983, 1939 2. Ming SC, Levitan R: Acute hemorrhagic necrosis of the gastrointestinal tract. N Engl J Med 263:59-65, 1960 3. Freiman DG: Hemorrhagic necrosis of the gastrointestinal tract. Circulation 32:329-331, 1965 4. Fogarty TJ, Fletcher WS: Genesis of non-occlusive mesenteric ischemia. Am J Surg 111:130-134, 1965 5. Haglund W, Hulten L, Ahren C, et al: Mucosal lesions in the human small intestine in shock. Gut 16:979-984, 1975 6. Aldrete JS, Han SY, Laws HL, Kirklin JW: Intestinal infarction complicating low cardiac output states. Surg Gynecol Obstet 144:371, 1977 7. Bounous G, Hampson LG, Gurd FM: Cellular nucleotides in hemorrhagic shock: Relationship of intestinal metabolic changes to hemorrhagic enteritis and the barrier function of intestinal mucosa. Ann Surg 160:650-666, 1964 8. Bounous G, Brown R, Mulder D, et al: Abolition of"tryptic enteritis" in the shocked dog. Arch Surg 91:371-375, 1965 9. Bounous G, McArdle AH, Hodges DM, et al: Biosynthesis of intestinal mucin in shock. Ann Surg 164:13-22, 1966
892
10. Henry JN, McArdle AH, Scott HJ: A study of the acute and chronic respiratory pathophysiology of hemorrhagic shock. J Thorac Cardiovasc Surg 54:666-678, I967 11. Williams LF, Anastasia LF, Hasiotis CA, et al: Experimental non-occlusive mesenteric ischemia: therapeutic observations. Am J Surg 115:82-86, 1968 12. Tiberio G, Cagliani P, Parmeggiani A, et al: Sur la pr6vention de l'ent6rite n6crotico-h6morragique provoqu6e par le choc hypovolh6mique irr6versible exp6rimental. Lyon Chir 64:605-613, 1968 13. Laufman H: Discussion. Am J Surg 115:87, 1968 14. Golden PF, Jane JA: Survival following profound hypovolemia. Role of heart, lung and brain. J Trauma 9:784-795, 1969 15. Mackay PA, Burgess JH, Finlayson MH, et al: Hypoxemia and atelectasis in experimental hemorrhagic shock: Its decrease by periodic hyperinflation of the lungs. Can J Surg 12:351-357, 1969 16. Smith EE, Crowell JW, Moran CJ, et al: Intestinal fluid loss in dogs during irreversible hemorrhagic shock. Surg Gynecol Obstet 125:45-48, 1967 17. Soma LR, Neufeld GR, Dodd DC, et al: Pulmonary function in hemorrhagic shock: The effect of pancreatic ligation and blood filtration. Ann Surg 179:395-40I, 1974 18. Haglund U, Hulten L, Ahren C, et al: The intestinal mucosal lesions in shock. Eur Surg Res 8:435-447, 1974 19. Kondo M, Yoshikawa T, Takemura S, Yokoe N, Kawai K, Masuda M: Hemorrhagic necrosis of the intestinal mucosa associated with disseminated intravascular coagulation. Digestion 17:38-45, 1978 20. Manabe T, Suzuki T, Honjo I: Role of the pancreas in organ blood flow during shock. Surg Gynecol Obstet 146:577-582, 1978 21. Bounous G, Menard D, De Medicis E: Role of pancreatic proteases in the pathogenesis of ischemic enteropathy. Gastroenterology 73:102-108, 1977 22. Bounous G, Proulx B, Konok G: The role of bile and pancreatic proteases in the pathogenesis of ischemic enteropathy. Int J Clin Pharmacol Biopharm (in press) 23. Alpers DH, Tedesco FJ: The possible role of pancreatic proteases in the turnover of intestinal brush border proteins. Biochim Biophys Acta 401:28-40, 1975 24. Maestracci D: Enzymic solubilization of the human intestinal brush border membrane enzymes. Biochim Biophys Acta 433:469-481, 1976 25. Vasseur M, Ferrard G, Pousse A: Rat intestinal brush border enzymes release by deoxycholate in vivo. Pfluegers Arch 373:133-138, 1978
Digestive Diseases and Sciences, Vol. 24, No. 11 (November 1979)
FLEXIBLE SIGMOIDOSCOPY To The Editor: The paper by Dr. Winawer and his associates (24:277-281) on the use of flexible sigmoidoscopy echoes our sentiments after using this instrument in more than one hundred patients during the past eight months. We, too, perform the examination as an outpatient procedure, usually as a prelude to a barium enema on the same morning. However, we always use the left lateral position since this is more readily accepted by the patient and is less "strenuous," especially in the elderly. Furthermore, we reach a distance of 65 cm (the full length of the instrument) in well over 90% of our patients and well within a period of ten minutes. As " s p a s m " is the usual reason one fails to reach this level we premedicate our patients with 5-10 mg of intravenous diazepam (Valium). Perhaps, this is why so many of our patients "recommend" us to their friends! LEE SATALINE, MD Chief, G.1. Section TERRI
GOFFRED
GI Assistant Bradley Memorial Hospital and Health Center Southington, Connecticut
PHYSIOLOGICAL BASIS OF ISCHEMIC ENTEROPATHY To The Editor: In recent years there has been an increased interest in the specific susceptibility of the intestinal mucosa to low flow states (1-21). In this letter I propose a theory relating this phenomenon to some specific aspects of intestinal physiology. Several years ago we demonstrated that changes induced by circulatory insufficiency in the small bowel mucosa of the dog may include an increased vulnerability to the digestive action of trypsin and chymotrypsin: hemorrhagic necrosis of the mucosa induced by shock is minimized by previous inhibition of trypsin and chymotx:ypsin in the intestinal lumen (7) or by previous ligation of the pancreatic ducts (8). It was postulated that such changes were
somehow related to the disappearance of the mucus coat covering the lining epithelium observed in the early stages of severe hypotension (9). Numerous studies, carried out in four animal species, have since confirmed these original findings (10-20). Although these studies provide evidence that pancreatic proteases play an important role in the advanced phase of ischemia, they failed to define the relative role of different pancreatic enzymes in the early as well as advanced phases of ischemia. Recent experiments in rats have helped us to better u n d e r s t a n d the role of pancreatic endopeptidases and bile in the pathogenesis of the small bowel mucosal lesion during ischemia (21, 22). The loss of total brush border proteins and activities of sucrase, trehalase, glutamyltransferase (GGT Pase) and leucylnaphtylamidase (LNA ase) observed after 45 min of ischemia is substantially reduced by previous lavage of the lumen by saline perfusion, but it is not influenced by prior inhibition of luminal trypsin and chymotrypsin with Trasylol (21). Thus factors within the lumen other than trypsin are partially responsible for the loss of brush border proteins which occurs after short-term occlusion of the mesenteric artery. The effect of elastase was estimated by either adding, before ischemia, a physiological amount of the enzym e to the lumen after complete intestinal perfusion (21) or by previous inhibition of elastase with turkey ovomucoid (22): while the former treatment enhances the loss of brush border proteins, the latter substantially reduces it. The role of bile salts was investigated by adding cuemid to the lumen before ischemia: this partially protects the brush border from the effects of 45 min ischemia (22). When mesenteric artery occlusion was prolonged to 100 min, previous selective inhibition of luminal trypsin and chymotrypsin with Trasylol minimized its effects on loss of mucosal weight, DNA, and proteins (21). Our observations following 45 rain ischemia are consistent with recent physiological experiments by Alpers and Tedesco (23) in rats and Maestracci (24) in man, showing that pancreatic elastase plays a natural role in stripping glycoproteins from the brush border. A similar role for bile salts was suggested by Vasseur et al (25). In conclusion, our biochemical data, consistent with the morphological picture, suggest the following theory:
Digestive Diseases and Sciences, Vol. 24, No. 11 (November 1979) 0163-2116/79/1100-0891503.00/1 9 1979 Digestive Disease Systems, Inc.
891
L E T T E R S TO T H E EDITOR The physiological loss of brush border glycoproteins, produced by the action of pancreatic elastase a n d bile s a l t s , s u d d e n l y b e c o m e s a p a t h o l o g i c a l p h e n o m e n o n if i m p a i r m e n t o f m e s e n t e r i c b l o o d flow p r e v e n t s t h e s t e a d y r e g e n e r a t i o n o f t h e s e front-line constituents of the small bowel mucosa. I n t h e initial p h a s e o f i s c h e m i a , t h e s e f a c t o r s w i t h i n t h e i n t e s t i n a l l u m e n c o n t r i b u t e s u b s t a n t i a l l y to t h e loss of brush border proteins. After the disa p p e a r a n c e o f t h e b r u s h b o r d e r , in t h e a d v a n c e d phase of ischemia, the protection by trypsin-resist a n t g l y c o p r o t e i n s is l o s t ; h e n c e t h e u n d e r l y i n g structures are accessible to the digestive action of t h e p a n c r e a t i c e n d o p e p t i d a s e s p r e s e n t a l o n g t h e intestinal wall and lumen. GUSTAVO BOUNOUS, M D C e n t r e H o s p i t a l i e r Universitaire Sherbrooke, QuObec, C a n a d a REFERENCES
1. Penner A, Bernhein AI: Acute postoperative enterocolitis. A study on the pathologic nature of shock. Arch Patho127:966983, 1939 2. Ming SC, Levitan R: Acute hemorrhagic necrosis of the gastrointestinal tract. N Engl J Med 263:59-65, 1960 3. Freiman DG: Hemorrhagic necrosis of the gastrointestinal tract. Circulation 32:329-331, 1965 4. Fogarty TJ, Fletcher WS: Genesis of non-occlusive mesenteric ischemia. Am J Surg 111:130-134, 1965 5. Haglund W, Hulten L, Ahren C, et al: Mucosal lesions in the human small intestine in shock. Gut 16:979-984, 1975 6. Aldrete JS, Han SY, Laws HL, Kirklin JW: Intestinal infarction complicating low cardiac output states. Surg Gynecol Obstet 144:371, 1977 7. Bounous G, Hampson LG, Gurd FM: Cellular nucleotides in hemorrhagic shock: Relationship of intestinal metabolic changes to hemorrhagic enteritis and the barrier function of intestinal mucosa. Ann Surg 160:650-666, 1964 8. Bounous G, Brown R, Mulder D, et al: Abolition of"tryptic enteritis" in the shocked dog. Arch Surg 91:371-375, 1965 9. Bounous G, McArdle AH, Hodges DM, et al: Biosynthesis of intestinal mucin in shock. Ann Surg 164:13-22, 1966
892
10. Henry JN, McArdle AH, Scott HJ: A study of the acute and chronic respiratory pathophysiology of hemorrhagic shock. J Thorac Cardiovasc Surg 54:666-678, I967 11. Williams LF, Anastasia LF, Hasiotis CA, et al: Experimental non-occlusive mesenteric ischemia: therapeutic observations. Am J Surg 115:82-86, 1968 12. Tiberio G, Cagliani P, Parmeggiani A, et al: Sur la pr6vention de l'ent6rite n6crotico-h6morragique provoqu6e par le choc hypovolh6mique irr6versible exp6rimental. Lyon Chir 64:605-613, 1968 13. Laufman H: Discussion. Am J Surg 115:87, 1968 14. Golden PF, Jane JA: Survival following profound hypovolemia. Role of heart, lung and brain. J Trauma 9:784-795, 1969 15. Mackay PA, Burgess JH, Finlayson MH, et al: Hypoxemia and atelectasis in experimental hemorrhagic shock: Its decrease by periodic hyperinflation of the lungs. Can J Surg 12:351-357, 1969 16. Smith EE, Crowell JW, Moran CJ, et al: Intestinal fluid loss in dogs during irreversible hemorrhagic shock. Surg Gynecol Obstet 125:45-48, 1967 17. Soma LR, Neufeld GR, Dodd DC, et al: Pulmonary function in hemorrhagic shock: The effect of pancreatic ligation and blood filtration. Ann Surg 179:395-40I, 1974 18. Haglund U, Hulten L, Ahren C, et al: The intestinal mucosal lesions in shock. Eur Surg Res 8:435-447, 1974 19. Kondo M, Yoshikawa T, Takemura S, Yokoe N, Kawai K, Masuda M: Hemorrhagic necrosis of the intestinal mucosa associated with disseminated intravascular coagulation. Digestion 17:38-45, 1978 20. Manabe T, Suzuki T, Honjo I: Role of the pancreas in organ blood flow during shock. Surg Gynecol Obstet 146:577-582, 1978 21. Bounous G, Menard D, De Medicis E: Role of pancreatic proteases in the pathogenesis of ischemic enteropathy. Gastroenterology 73:102-108, 1977 22. Bounous G, Proulx B, Konok G: The role of bile and pancreatic proteases in the pathogenesis of ischemic enteropathy. Int J Clin Pharmacol Biopharm (in press) 23. Alpers DH, Tedesco FJ: The possible role of pancreatic proteases in the turnover of intestinal brush border proteins. Biochim Biophys Acta 401:28-40, 1975 24. Maestracci D: Enzymic solubilization of the human intestinal brush border membrane enzymes. Biochim Biophys Acta 433:469-481, 1976 25. Vasseur M, Ferrard G, Pousse A: Rat intestinal brush border enzymes release by deoxycholate in vivo. Pfluegers Arch 373:133-138, 1978
Digestive Diseases and Sciences, Vol. 24, No. 11 (November 1979)
