- Email: [email protected]
Absorptive hyperemia
May 1995
SELECTED SUMMARIES 1599
patients with bloody diarrhea. Cultures for E. coli O157:H7 should be requested in those patients, particularly because we know that its incidence has increased over the last several years. Finally, because there is no effective treatment and no way to prevent hemolytic-uremic syndrome, prevention of infection is critical. Consumers should avoid raw milk and poorly cooked beef. However, the meat industry will also need substantial changes in its slaughter and inspection routines to provide a safe product. L. HORNSBY-LEWIS, M.D. [A Consensus Conference on E. coli O157:H7 was held in July 1994, and a statement of its conclusions will be published in GASTROENTEROmG¥.--Selected Summaries Editor] Reply. Clinicians should be reminded that it is not at all clear that the majority of all persons infected with E. coli O157:H7 develop bloody diarrhea. Although it is certainly true in the majority of both diagnosed and reported infections, intensified case finding has identified significant numbers of persons with mild and even asymptomatic infections in each of the seven Oregon outbreaks we have worked on since 1990. For obvious reasons, less serious illnesses are generally less likely to be diagnosed and reported. At this point, we lack comprehensive data about the proportion of infected persons who develop symptoms, much less bloody diarrhea. Similarly, it is not clear that susceptibility to infection or illness varies dramatically with age. Surveillance data in Oregon and other jurisdictions on their face do show a higher incidence in children under 10 years old (and particularly under 5) than in older persons, but the magnitude of that difference is not great. However, there is significant potential for bias in surveillance data, and the simple explanation may be no more profound than that parents are more likely to consult a physician about diarrhea (bloody or otherwise) in a 3-year-old than they would about similar symptoms in themselves. That said, it does seem that young children and the elderly infected with E. coli O157:H7 are at relatively increased risk of developing more serious complications such as hemolytic-uremic syndrome or thrombotic thrombocytopenic purpura. Although consumption of fecally contaminated recreational water is probably a relatively uncommon mode of enteric disease transmission, it may be part of the reason for the summer peak of several such infections. We were somewhat surprised to note that transmission of both E. coli O157:H7 and Shigella continued over more than 3 weeks, with no evidence suggesting recurrent introduction of these pathogens. This suggests a low infectious dose for both organisms and highlights the importance of minimizing fecal contamination of swimming areas, particularly unchlorinated ones. There are obvious implications for the management of swimming areas implicated as a source of transmission. Let's not throw out the baby with the lake water, however. To reduce the incidence ofE. coli O 157 :H7 infections, the simple message to get across to patients is the need to handle uncooked meat carefully (to avoid cross-contamination), cook meat adequately, avoid raw milk, and, not least of all, wash hands thoroughly to eliminate person-toperson transmission. Clinicians can also help by considering E. coli O 157:H7 in the differential diagnosis of diarrheal disease, particularly if bloody, and by prompt reporting of suspected infections to public health agencies. W. E. KEENE, PH.D., M.P.H.
ABSORPTIVE HYPEREMIA SteenbergenJM, LashJM, Bohlen H G (Department of Physiology and Biophysics, Indiana University Medical School, Indianapo-
lis, Indiana). Role of a lymphatic system in glucose absorption and the accompanying microvascular hyperemia. A m J Physiol 1994; 267 : G 5 2 9 - G535 (October). During absorption, epithelial cells transport glucose and sodium from the l u m e n into the submucosal interstitium where tonicity increases as a result. The mechanisms by which interstitial hypertonicity is linked to the dilatation of s u b m u cosal arterioles characteristic of absorptive hyperemia needs better definition. Preliminary data point to a role for the submucosal lymphatic system and its release of the endothelialderived relaxing factor. To examine that role for the hyperemia during glucose absorption, the investigators used an ex vivo preparation of the rat ileum. The bowel was slit longitudinally and stretched over a translucent pedestal. Submucosal arterioles were observed by bright-field microscopy of the transillumihated tissue, and their inner diameters were measured after image digitization. The hemoglobin oxygen saturation for a second-order arteriole and its corresponding venule were measured, and blood was pipetted from the first-order venule draining that territory for determination of osmolarity. After a control period in which the mucosal and serosal surfaces were superfused with physiological buffer, the mucosal side was superfused with buffer containing isotonic glucose for 10 m i n utes. All measurements were repeated after blocking flow in the lymph system; the passage of lymph from the mucosa to the submucosa was effectively blocked for several hours by the puncture of lymphatic vessels to fill them with oil. Intestinal contractions were suppressed with isoproteronol. Glucose absorption was associated with a doubling of the arteriovenous oxygen difference, a 5 0 - m O s m increase in venous blood osmolarity, and a 17% increase in the diameter of the second-order arterioles. Blockage of the lymphatic system did not eliminate the vasodilation or the increases in arteriovenous oxygen difference and blood osmolarity associated with glucose absorption. Lymph flow is an order of magnitude smaller than blood flow during the absorption of glucose and even of lipids. This plus the high permeability of submucosal venules for small molecules and the ability of venular endothelium to release endothelial-derived relaxing factor make it possible that absorptive hyperemia originates with compounds released into the interstitium from venules rather than from lymphatics. Comment. Hyperemia is a common phenomenon in the gastrointestinal tract, but the mechanisms mediating it remain poorly understood. Nervous mechanisms have been proposed in the hyperemic response to injury (Gastroenterology 1990;98:838-848, Gastroenterology 1986;91:975-981). By negating a role for the lymphatic system, the present study might invite speculation on the importance of nervous factors in absorptive hyperemia as well. The milieu provided by the interstitium has been intensely studied during the last decade, particularly by Granger et al. (Am J Physiol 1981; 240:G343, Am J Physiol 1978;232:E13, Am J Physiol 1984;247:G161, Am J Physiol 1982;242:G194). The submucosal interstitium constitutes a pool that is fed by fluid that is filtered from capillaries and absorbed by the epithelium; it is drained by capillaries and lymphatics. The interstitium is a noncellular domain with a gel structure provided
1600
SELECTED SUMMARIES
by collagen fibers and a tangle of mucopolysaccharide chains. As the interstitium is hydrated, the gel imbibes water into a mesh structure. The permeability of the mesh to macromolecules depends on its hydration. The interstitium of the lamina propria is separated from that of the submucosa by the muscularis mucosae. The muscularis mucnsae and the muscle coat probably spin off many of the interstitial structures. Their physical links to the connective tissue in the lamina propria and submucosa make it likely that the mechanical activity of the muscularis mucosae and propria affect the structure and function of the interstitial space. Baseline tension or muscle tone might alter the configuration, the pressure, and other important aspects of the interstitial space. Phasic contractions are likely to compress the interstitium and hence increase the pressure gradient between it and lymphatic capillaries. During fluid absorption, the central lacteals of intestinal villi fill during the relaxation phase of villous contractions (Am J Physiol 1971;221:488). Additional interactions have been postulated (Q J Exp Physiol 1977;42:207). Controversy and uncertainty persist because experimental manipulations target not only the smooth muscle of the mucosa but also that of blood and lymph vessels. Furthermore, hitherto quantifiable parameters of contractions, of the physiological state of the interstitium, and of generation and flow of lymph may not match because some might define only shortlived bursts and others only gradual changes. Still, given the great efforts of the present study to validate methodology, it is a pity that the investigators paralyzed their preparations. This might have led them to underestimate the role the lymphatics play in the absorption of glucose in the normally contracting intestine. Hopefully, the investigators will be able to find novel experimental solutions to this issue. KONRAD SCHULZE-DELRIEU, M.D.
Reply. Regulation of intestinal blood flow during nutrient absorption has been attributed to many mechanisms, one of which is transfer of the hypertonic conditions in the villus to the environment of the resistance vessels of the submucosa through venular blood and the flow of lymph. Contrary to the comments of Dr. Schulze-Delrieu about our study, the intestine is not paralyzed: the motility is simply suppressed sufficiently to allow use of micropipette or optical instrumentation. Prior studies (AmJ Physiol 1989;277:G438-G446) indicate that stoppage of bowel motility essentially eliminates submucosal lymph hyperosmolarity during absorption and compromises absorption, as judged in the current study by the trivial decline in venular blood saturation of hemoglobin and minimal vasodilation. This clearly indicates that some aspect of lymph formation and subsequent propulsion to the submucosa is important to intestinal vascular regulation. Appropriate suppression of motility does not appreciably disturb resting vascular resistance (Am J Physiol 1987;G787-G797), and bowel motility continues to cycle lymphatic pressures (Am J Physiol 1989;257:G438-G446), which is important because lymphatic vessels, including lacteals of dogs, cats, rats, and rabbits, are not themselves actively motile and rely on bowel smooth muscle for pumping the lymph. Once the lymph vessels exit the bowel wall, the vessels become self-motile. Both lymph and venular vessels transport 340-370 mOsm fluid to the submucosa from the villous lacteals during glucose and oleic acid absorption. Artificial perfusion of the submucosal lymphatic system with a comparable sodium hypertonic medium causes approximately the same amount of arteriolar dilation as during absorptive hyperemia (Am J Physiol 1993; 265:H323-H328). About half of the vasodilation is caused by nitric oxide or a closely related species released in response to sodium hyperosmnlarity; equivalent hyperos-
GASTROENTEROLOGY Vol. 108, No. 5
molarity caused by mannitol causes about half as much dilation by a mechanism independent of nitric oxide. In the study commented on by Dr. Schulze-Delrieu, we showed that if submucosal lymph vessels are mechanically blocked, the vasodilation associated with absorption proceeds about normally. This probably can occur because venular blood returning from the villi contains sufficient hypertonic material, as well as other vasoactive materials, to cause dilation of the submucosal arterioles. This is an important observation because we now know that lymph and venular blood both are equally capable of influencing dilation of the submucosal arteriolar network during absorptive hyperemia. We know from the distribution of vascular resistance in the intestinal microvasculature that the submucosal arterioles dominate intestinal vascular resistance at rest (Am J Physiol 1987;273:G587-G595). Furthermore, these are the only vessels with sufficient ability to lower their vascular resistance to account for the typical 4 0 % - 8 0 % increase in intestinal blood flow during nutrient absorption. For example, maximum dilation of the villus vascular circuit cannot increase intestinal blood flow more than 15%-27 %; any flow response of higher magnitude requires the dilation of submucosal arterioles. To what extent neural, hormonal, osmotic, or some as yet to be found mechanism(s) coordinate communication of the needs of the villus to the resistance vasculature remains to be explored. However, we clearly have evidence that both sodium hypertonic lymph and venular blood are equivalent major components of the communication and dilatory mechanisms associated with absorptive hyperemia. H. GLEN BOHLEN, Ph.D.
ZOLLINGER-ELLISON SYNDROME: SURGERY SHOULD STILL PLAY AN IMPORTANT ROLE IN ITS MANAGEMENT Fraker DL, NortonJA, Alexander HR, Venzon DJ, Jensen RT (Surgical Metabolism Section, Surgery Branch, and Biostatistics and Data Management Section, National Cancer Institute, National Institutes of Health, Bethesda, Maryland; Departm e n t of Surgery, W a s h i n g t o n University, St. Louis, Missouri; and Digestive Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland). Surgery in Z o l l i n g e r - E l l i s o n syndrome alters the natural history of gastrinoma. Ann Surg 1994;220:320-330. A l t h o u g h symptoms of acid hypersecretion can be effectively managed medically in the Z o l l i n g e r - E l l i s o n syndrome with high-dose pharmacological therapy, cure of this disease still requires excision of the gastrinoma. Because biochemical cure is obtained only in a portion of patients and the neoplastic disease may be indolent in this syndrome, the ability of surgical resection of gastrinoma to alter or improve the subsequent development of hepatic metastases and mortality, which presently has not been defined, was assessed in the present study. One hundred twenty-four patients with the biochemical diagnosis of Z o l l i n g e r - E l l i s o n syndrome and without hepatic metastases on initial imaging studies were evaluated. Ninetyeight patients underwent surgical exploration for curative gastrinoma resection, and 26 patients were treated medically. Long-term follow-up regarding development of hepatic metastases and survival were then evaluated. Surgical exploration
SELECTED SUMMARIES 1599
patients with bloody diarrhea. Cultures for E. coli O157:H7 should be requested in those patients, particularly because we know that its incidence has increased over the last several years. Finally, because there is no effective treatment and no way to prevent hemolytic-uremic syndrome, prevention of infection is critical. Consumers should avoid raw milk and poorly cooked beef. However, the meat industry will also need substantial changes in its slaughter and inspection routines to provide a safe product. L. HORNSBY-LEWIS, M.D. [A Consensus Conference on E. coli O157:H7 was held in July 1994, and a statement of its conclusions will be published in GASTROENTEROmG¥.--Selected Summaries Editor] Reply. Clinicians should be reminded that it is not at all clear that the majority of all persons infected with E. coli O157:H7 develop bloody diarrhea. Although it is certainly true in the majority of both diagnosed and reported infections, intensified case finding has identified significant numbers of persons with mild and even asymptomatic infections in each of the seven Oregon outbreaks we have worked on since 1990. For obvious reasons, less serious illnesses are generally less likely to be diagnosed and reported. At this point, we lack comprehensive data about the proportion of infected persons who develop symptoms, much less bloody diarrhea. Similarly, it is not clear that susceptibility to infection or illness varies dramatically with age. Surveillance data in Oregon and other jurisdictions on their face do show a higher incidence in children under 10 years old (and particularly under 5) than in older persons, but the magnitude of that difference is not great. However, there is significant potential for bias in surveillance data, and the simple explanation may be no more profound than that parents are more likely to consult a physician about diarrhea (bloody or otherwise) in a 3-year-old than they would about similar symptoms in themselves. That said, it does seem that young children and the elderly infected with E. coli O157:H7 are at relatively increased risk of developing more serious complications such as hemolytic-uremic syndrome or thrombotic thrombocytopenic purpura. Although consumption of fecally contaminated recreational water is probably a relatively uncommon mode of enteric disease transmission, it may be part of the reason for the summer peak of several such infections. We were somewhat surprised to note that transmission of both E. coli O157:H7 and Shigella continued over more than 3 weeks, with no evidence suggesting recurrent introduction of these pathogens. This suggests a low infectious dose for both organisms and highlights the importance of minimizing fecal contamination of swimming areas, particularly unchlorinated ones. There are obvious implications for the management of swimming areas implicated as a source of transmission. Let's not throw out the baby with the lake water, however. To reduce the incidence ofE. coli O 157 :H7 infections, the simple message to get across to patients is the need to handle uncooked meat carefully (to avoid cross-contamination), cook meat adequately, avoid raw milk, and, not least of all, wash hands thoroughly to eliminate person-toperson transmission. Clinicians can also help by considering E. coli O 157:H7 in the differential diagnosis of diarrheal disease, particularly if bloody, and by prompt reporting of suspected infections to public health agencies. W. E. KEENE, PH.D., M.P.H.
ABSORPTIVE HYPEREMIA SteenbergenJM, LashJM, Bohlen H G (Department of Physiology and Biophysics, Indiana University Medical School, Indianapo-
lis, Indiana). Role of a lymphatic system in glucose absorption and the accompanying microvascular hyperemia. A m J Physiol 1994; 267 : G 5 2 9 - G535 (October). During absorption, epithelial cells transport glucose and sodium from the l u m e n into the submucosal interstitium where tonicity increases as a result. The mechanisms by which interstitial hypertonicity is linked to the dilatation of s u b m u cosal arterioles characteristic of absorptive hyperemia needs better definition. Preliminary data point to a role for the submucosal lymphatic system and its release of the endothelialderived relaxing factor. To examine that role for the hyperemia during glucose absorption, the investigators used an ex vivo preparation of the rat ileum. The bowel was slit longitudinally and stretched over a translucent pedestal. Submucosal arterioles were observed by bright-field microscopy of the transillumihated tissue, and their inner diameters were measured after image digitization. The hemoglobin oxygen saturation for a second-order arteriole and its corresponding venule were measured, and blood was pipetted from the first-order venule draining that territory for determination of osmolarity. After a control period in which the mucosal and serosal surfaces were superfused with physiological buffer, the mucosal side was superfused with buffer containing isotonic glucose for 10 m i n utes. All measurements were repeated after blocking flow in the lymph system; the passage of lymph from the mucosa to the submucosa was effectively blocked for several hours by the puncture of lymphatic vessels to fill them with oil. Intestinal contractions were suppressed with isoproteronol. Glucose absorption was associated with a doubling of the arteriovenous oxygen difference, a 5 0 - m O s m increase in venous blood osmolarity, and a 17% increase in the diameter of the second-order arterioles. Blockage of the lymphatic system did not eliminate the vasodilation or the increases in arteriovenous oxygen difference and blood osmolarity associated with glucose absorption. Lymph flow is an order of magnitude smaller than blood flow during the absorption of glucose and even of lipids. This plus the high permeability of submucosal venules for small molecules and the ability of venular endothelium to release endothelial-derived relaxing factor make it possible that absorptive hyperemia originates with compounds released into the interstitium from venules rather than from lymphatics. Comment. Hyperemia is a common phenomenon in the gastrointestinal tract, but the mechanisms mediating it remain poorly understood. Nervous mechanisms have been proposed in the hyperemic response to injury (Gastroenterology 1990;98:838-848, Gastroenterology 1986;91:975-981). By negating a role for the lymphatic system, the present study might invite speculation on the importance of nervous factors in absorptive hyperemia as well. The milieu provided by the interstitium has been intensely studied during the last decade, particularly by Granger et al. (Am J Physiol 1981; 240:G343, Am J Physiol 1978;232:E13, Am J Physiol 1984;247:G161, Am J Physiol 1982;242:G194). The submucosal interstitium constitutes a pool that is fed by fluid that is filtered from capillaries and absorbed by the epithelium; it is drained by capillaries and lymphatics. The interstitium is a noncellular domain with a gel structure provided
1600
SELECTED SUMMARIES
by collagen fibers and a tangle of mucopolysaccharide chains. As the interstitium is hydrated, the gel imbibes water into a mesh structure. The permeability of the mesh to macromolecules depends on its hydration. The interstitium of the lamina propria is separated from that of the submucosa by the muscularis mucosae. The muscularis mucnsae and the muscle coat probably spin off many of the interstitial structures. Their physical links to the connective tissue in the lamina propria and submucosa make it likely that the mechanical activity of the muscularis mucosae and propria affect the structure and function of the interstitial space. Baseline tension or muscle tone might alter the configuration, the pressure, and other important aspects of the interstitial space. Phasic contractions are likely to compress the interstitium and hence increase the pressure gradient between it and lymphatic capillaries. During fluid absorption, the central lacteals of intestinal villi fill during the relaxation phase of villous contractions (Am J Physiol 1971;221:488). Additional interactions have been postulated (Q J Exp Physiol 1977;42:207). Controversy and uncertainty persist because experimental manipulations target not only the smooth muscle of the mucosa but also that of blood and lymph vessels. Furthermore, hitherto quantifiable parameters of contractions, of the physiological state of the interstitium, and of generation and flow of lymph may not match because some might define only shortlived bursts and others only gradual changes. Still, given the great efforts of the present study to validate methodology, it is a pity that the investigators paralyzed their preparations. This might have led them to underestimate the role the lymphatics play in the absorption of glucose in the normally contracting intestine. Hopefully, the investigators will be able to find novel experimental solutions to this issue. KONRAD SCHULZE-DELRIEU, M.D.
Reply. Regulation of intestinal blood flow during nutrient absorption has been attributed to many mechanisms, one of which is transfer of the hypertonic conditions in the villus to the environment of the resistance vessels of the submucosa through venular blood and the flow of lymph. Contrary to the comments of Dr. Schulze-Delrieu about our study, the intestine is not paralyzed: the motility is simply suppressed sufficiently to allow use of micropipette or optical instrumentation. Prior studies (AmJ Physiol 1989;277:G438-G446) indicate that stoppage of bowel motility essentially eliminates submucosal lymph hyperosmolarity during absorption and compromises absorption, as judged in the current study by the trivial decline in venular blood saturation of hemoglobin and minimal vasodilation. This clearly indicates that some aspect of lymph formation and subsequent propulsion to the submucosa is important to intestinal vascular regulation. Appropriate suppression of motility does not appreciably disturb resting vascular resistance (Am J Physiol 1987;G787-G797), and bowel motility continues to cycle lymphatic pressures (Am J Physiol 1989;257:G438-G446), which is important because lymphatic vessels, including lacteals of dogs, cats, rats, and rabbits, are not themselves actively motile and rely on bowel smooth muscle for pumping the lymph. Once the lymph vessels exit the bowel wall, the vessels become self-motile. Both lymph and venular vessels transport 340-370 mOsm fluid to the submucosa from the villous lacteals during glucose and oleic acid absorption. Artificial perfusion of the submucosal lymphatic system with a comparable sodium hypertonic medium causes approximately the same amount of arteriolar dilation as during absorptive hyperemia (Am J Physiol 1993; 265:H323-H328). About half of the vasodilation is caused by nitric oxide or a closely related species released in response to sodium hyperosmnlarity; equivalent hyperos-
GASTROENTEROLOGY Vol. 108, No. 5
molarity caused by mannitol causes about half as much dilation by a mechanism independent of nitric oxide. In the study commented on by Dr. Schulze-Delrieu, we showed that if submucosal lymph vessels are mechanically blocked, the vasodilation associated with absorption proceeds about normally. This probably can occur because venular blood returning from the villi contains sufficient hypertonic material, as well as other vasoactive materials, to cause dilation of the submucosal arterioles. This is an important observation because we now know that lymph and venular blood both are equally capable of influencing dilation of the submucosal arteriolar network during absorptive hyperemia. We know from the distribution of vascular resistance in the intestinal microvasculature that the submucosal arterioles dominate intestinal vascular resistance at rest (Am J Physiol 1987;273:G587-G595). Furthermore, these are the only vessels with sufficient ability to lower their vascular resistance to account for the typical 4 0 % - 8 0 % increase in intestinal blood flow during nutrient absorption. For example, maximum dilation of the villus vascular circuit cannot increase intestinal blood flow more than 15%-27 %; any flow response of higher magnitude requires the dilation of submucosal arterioles. To what extent neural, hormonal, osmotic, or some as yet to be found mechanism(s) coordinate communication of the needs of the villus to the resistance vasculature remains to be explored. However, we clearly have evidence that both sodium hypertonic lymph and venular blood are equivalent major components of the communication and dilatory mechanisms associated with absorptive hyperemia. H. GLEN BOHLEN, Ph.D.
ZOLLINGER-ELLISON SYNDROME: SURGERY SHOULD STILL PLAY AN IMPORTANT ROLE IN ITS MANAGEMENT Fraker DL, NortonJA, Alexander HR, Venzon DJ, Jensen RT (Surgical Metabolism Section, Surgery Branch, and Biostatistics and Data Management Section, National Cancer Institute, National Institutes of Health, Bethesda, Maryland; Departm e n t of Surgery, W a s h i n g t o n University, St. Louis, Missouri; and Digestive Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland). Surgery in Z o l l i n g e r - E l l i s o n syndrome alters the natural history of gastrinoma. Ann Surg 1994;220:320-330. A l t h o u g h symptoms of acid hypersecretion can be effectively managed medically in the Z o l l i n g e r - E l l i s o n syndrome with high-dose pharmacological therapy, cure of this disease still requires excision of the gastrinoma. Because biochemical cure is obtained only in a portion of patients and the neoplastic disease may be indolent in this syndrome, the ability of surgical resection of gastrinoma to alter or improve the subsequent development of hepatic metastases and mortality, which presently has not been defined, was assessed in the present study. One hundred twenty-four patients with the biochemical diagnosis of Z o l l i n g e r - E l l i s o n syndrome and without hepatic metastases on initial imaging studies were evaluated. Ninetyeight patients underwent surgical exploration for curative gastrinoma resection, and 26 patients were treated medically. Long-term follow-up regarding development of hepatic metastases and survival were then evaluated. Surgical exploration