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Diseases of the pancreas
GASTnm:NTEHOI.OGY 69: 1088- 1094, 1975 Copyright@ 1975 by The Williams & Wilkins Co.
Vol. 69, No.5 Printed in U.S .A.
WORK GROUP III
Diseases of the pancreas I. Research related to pancreatitis A. Epidemiology B. Genetics C. Pathogenesis D. Diagnosis E. Treatment II. Basic research related to the pancreas III. Priorities
The commonest diseases of the exocrine pancreas are dramatic, debilitating, and deadly: acute and chronic inf1ammation (pancreatitis) and cancer of the gland . We shall concern ourselves in this report with pancreatitis. There is undoubtedly a connection of unknown nature between alcoholism, inf1ammation of the pancreas, and cancer of the pancreas. Also, diseases of the exocrine or digestive portion of the pancreas affect the endocrine or hormoneproducing portion of the organ. But again we do not have this aspect as our major concern in this report. Epidemiological data indicate that patients with pancreatic diseases constitute a significant portion of individuals suffering from digestive disorders. Acute and chronic pancreatitis have a worldwide incidence, and in the United States the form of the disease associated with chronic alcoholism is a major health problem. The pancreas manufactures, stores, and "packages" for export into the intestinal tract the enzymes required for digestion of the major classes of foodstuffs: sugars, proteins , and fats. In acute pancreatitis it is as if this factory explodes and digestive enzymes no longer in safe "packages" attack the factory itself. We know so little about pancreatic disease because we know relatively little about how the normal pancreas works. This inadequacy results largely from the fact that research on the pancreas has lagged behind that of other digestive or-
gans. The lack of research on the pancreas may be explained in part by the erroneous notion that exocrine pancreatic diseases are uncommon, by the inaccessibility of the pancreas for clinical investigation, and by the lack of specific and rapid methods to study pancreatic function. As a result, our current diagnostic tools remain crudely qualitative, our ability to diagnose early stages of pancreatic disease is nonexistent, and the regimen of therapy and our therapeutic results have not changed over the past 3 decades . This report emphasizes the point that technical and methodological capabilities necessary for advancing knowledge of the digestive pancreas are available and that appreciable insight into pancreatic runetion and disease are within the grasp of the investigative gastroenterologist. The substance of this report is presented under two major subheadings: (I) applied research directly related to diseases of the pancreas, and (II) basic research related to understanding pancreatic function. It is our conviction that if more fundamental information were available concerning pancreatic function at the organ and cellular level it would find application in improvements in diagnosis and treatment of pancreatic disease. The subheadings dealing with diseases of the pancreas have been grouped according to etiology, pathogenesis, diagnosis, and therapy. The subheadings dealing with fundamental research are presented in a more problem-oriented
1088
November 1975
DISEASES OF THE PANCREAS
manner. We conclude with a brief summary of the present status of the field and a statement about proposed future research. I. Research Related to Pancreatitis Research should be directed toward applying available technology to studies of pancreatic diseases. The most common forms of human exocrine pancreatic disease, acute and chronic pancreatitis, probably represent a continuum of the same pathophysiological process, that is, inflammatory destruction of the pancreas leading to a loss of both exocrine and endocrine functions.
A. Epidemiology Epidemiological information about pancreatitis is limited. Available studies indicate that pancreatitis has a worldwide distribution, with considerable variation in its incidence in different parts of the world. Epidemiological studies should be conducted to identify target or index persons and to determine what characteristics predispose certain individuals or groups of individuals to the development of pancreatitis. Especially the roles of diet, alcohol, exposure to environmental pollutants, and regional factors should be weighed to identify those individuals who are at greatest risk for pancreatic disease. B. Genetics At least two forms of genetically transmitted pancreatitis are recognized. One is associated with aminoaciduria. In addition, there may be a number of related subtypes which have a metabolic etiology. A second form of hereditary pancreatitis seems to arise from structural abnormalities in the ductal system or sphincter. Further, it is likely that genetic factors play a major role in determining the predisposition of individuals to exocrine pancreatic disease. Many observations suggest a host-agent interaction and sensitivity of the host may be genetically determined. Thus, genetic differences may influence the susceptibility of the pancreas to injury from alcohol or drugs. This has been vividly demonstrated recently in the way
1089
patients with abnormalities of fat metabolism (various types of hyperlipidemia) may develop severe pancreatitis when taking birth control pills. Research should be directed toward understanding the mechanisms of inheritance of pancreatitis, as well as characterizing the molecular defect. Such studies should include cystic fibrosis of the pancreas and genetic relationships between exocrine and endocrine diseases.
C. Pathogenesis There is a curious paradox about the way in which pancreatitis develops. We know many factors which appear to trigger the attacks, yet we know very little about how they do this. These possible causative conditions include alcoholism, biliary tract disease, drugs (including diuretics), trauma, uremia, hypercalcemia, cigarette smoking, and disturbances of fat metabolism. While conditions or factors associated with pancreatitis are identifiable in many instances, the mechanisms at the cellular level have not been identified. In this country, alcoholism is the most common condition associated with pancreatitis. Over 70% of patients seen in one surgical clinic with acute or chronic pancreatitis were heavy consumers of alcohol, with no difference in incidence between sustained "heavy" drinkers and "binge" drinkers. Patients with pancreatitis who are excessive drinkers may represent a special subset of the total population of drinkers, since most alcoholics do not develop pancreatitis, and current medical experience suggests that alcoholic cirrhosis of the liver and alcoholic pancreatitis are infrequently associated. The reason for this difference is completely unknown. The most widely accepted hypothesis concerning the pathogenesis of acute pancreatitis is the autodigestion theory which proposes that proenzymes such as trypsinogen, chymotrypsinogen, or proelastase are activated within the pancreas, whereas in health they are not activated until they reach the intestine. These active enzymes then digest cellular membranes and cause
1090
WORK GROUP Ill
necrosis. Cellular injury and death results in the liberation of more injurious enzymes. There is damage of capillary basement membranes, increased capillary permeability, and engorgement of lymphatics. A cascade of injurious events ensues culminating in the development of acute hemorrhagic pancreatitis. These postulated events require validation; if they occur as described, then each event presents a potential opportunity to interrupt the cascade and stop the disease. The mechanism by which intrapancreatic activation of proenzymes occurs in pancreatitis is unknown. Pancreatic tissue and juice contain peptides that inhibit enzyme activity and enzyme activation. The structure of these inhibitors is now being elucidated. It will be important to determine whether a deficiency or abnormality of these inhibitors is a factor in the inappropriate activation of pancreatitis. Recent studies suggest that some of the enzymes concerned in blood clotting may participate in activation of pancreatic proenzymes and could be involved in the inappropriate activation seen in pancreatitis. The pancreatic enzymes often combine with specific inhibitors or with plasma proteins after they have been activated in pancreatitis. The introduction of radioimmunoassay of the pancreatic enzymes promises to make it possible to measure the proenzymes and their active forms in tissue, exudate, and blood in both normal and diseased states. Just as premature intrapancreatic activation of enzymes appears to be the central problem in acute pancreatitis, calcification of the pancreas is the central problem in chronic pancreatitis. Even when calcium deposits are not evident from X-rays, accumulation of calcium is a regular feature of chronic pancreatitis . Calcium is bound to and secreted with pancreatic enzymes, just as it is with other digestive enzymes such as salivary amylase and gastric pepsin, but the mechanisms that operate to cause accumulation of calcium carbonate in chronic pancreatitis are just beginning to be studied. Clinical studies should be undertaken to identify pathophysiologic events involved
Vol . 69, No.5
in human pancreatitis. These studies would, by necessity, be retrospective and largely descriptive. However, information derived from human studies could be applied to developing models in experimental animals. Studies using experimental animals might then define the molecular and pathophysiological events. The concept of a protective barrier at the ductal surface can be examined using morphological and ultrastructural methods. Methods can be developed to measure pancreatic intraductal pressure in patients and to determine whether increased intraductal pressure leads to escape of pancreatic enzymes and subsequent activation. Research should be directed at identifying molecular mechanisms involved in injury to pancreatic cells. The effects of steroids, tetracycline, and other drugs on the function of pancreatic acinar cells deserve investigation. Since chronic alcoholism is the most commonly recognized condition associated with pancreatitis, the effects of alcohol on the structure and function of pancreatic cells should be minutely and thoroughly defined. Does alcohol cause pancreatitis by altering lysosomal stability or does it alter metabolism in such a way as to produce cell injury? Surprisingly, despite considerable suggestive evidence that immunological factors play a role in the pathogenesis of common gastrointestinal disease~, such as ulcerative colitis, Crohn's disease, malabsorption syndromes, hepatitis, and pernicious anemia, only a little research has been devoted to this factor as a possible cause of pancreatitis . Techniques used in implicating immune factors in other disorders could be easily applied to the problem of pancreatitis. D. Diagnosis Methods employed in the diagnosis of acute and chronic pancreatitis have changed very little in the past 40 years. The diagnosis of acute pancreatitis is still based on history, physical examination, and supporting serum amylase or lipase. Serum enzymes such as trypsin , deoxyribonuclease, elastase, leucinoaminopeptidase,
November 1975
DISEASES OF THE PANCREAS
and others have been suggested to be of value in the diagnosis of pancreatic disease, but these laboratory tests have not gained broad acceptance. Pancreatic secretory function tests, although described more than 40 years ago, are presently used in only a few medical centers. Improvements in the radiological diagnosis of pancreatic disease include the use of duodenal hypotonography, pancreatic artedography, and more recently' endoscopic retrograde pancreatography; but these methods are indirect and time consuming. Pancreatic scanning techniques have been hindered by the lack of radioisotopes which specifically label the pancreas. Research directed at developing better methods for the diagnosis of acute and chronic pancreatic disease should have a high priority. A multicenter study should be established to evaluate and develop new methods for the diagnosis of acute pancreatitis. More precise knowledge should be obtained concerning factors which determine the degree and duration of serum enzyme elevations. Comparisons should also be made to determine which of the many serum enzymes are most helpful in the diagnosis of pancreatic disease. Isolation and characterization of the isozymes of pancreatic enzymes promises to greatly improve the specificity of these measurements for diagnosis. Radioimmunoassay will probably be a useful method for measurement of the individual isoenzymes. This emerging field of study deserves strong support. The technology of pancreatic secretory function tests needs standardization and simplification for widespread use in all hospital centers. Efforts should be directed at obtaining isotopically labeled compounds which concentrate specifically in the pancreas and are suitable for scanning techniques. Radiographic and arteriagraphic methods for visualizing the pancreas require improvement. For example, it has been shown recently that intra-arterial injection of a selective vasodilator, such as prostaglandin E,, into the superior mesenteric artery just prior to performing angiography of the intestinal circulation, greatly improves visualization of the mesenteric
1091
and portal veins near the head of the pancreas. The angiogram thus becomes more useful in diagnosing lesions of the pancreas which distort vascular architecture . Improvements in instrumentation for endoscopic retrograde pancreatography are also needed . Instruments should be devised which would allow visualization and biopsy of the pancreas through a peritoneoscope. The inability to diagnose exocrine pancreatic diseases at an early stage presents a major block to better recognition and management. With better instrumentation, better clinical studies of the pancreas might be obtained, analogous to the way in which needle biopsy of the liver opened up hepatology as a clinical field. New areas of pancreatic research need to be pursued through similar advances in instrumentation. The following areas offer promise. (a) Biopsy of the pancreas, either percutaneous or transduodenal; (b) endoscopic technics-better development of side-view instruments for pancreatic duct cannulation; (c) peritoneoscopy with visualization of the pancreas; (d) ultrasound and sonic procedures to identify pancreatic masses; (e) radioisotopic methods for labeling pancreatic tissue and for measuring exocrine secretion, blood flow, and enzyme syntheSIS.
E . Treatment The therapy of acute pancreatitis at present is primarily supportive and without a solid scientific basis. Recognized pathophysiologic abnormalities include: (a) hypovolemia, due in part to loss of fluid into the abdomen and retroperitoneal spaces; (b) hypoxemia, due in part to loss of lung compliance, depressed surfactin activity, and pulmonary edema; (c) irreversible shock due possibly to the release into the blood of vasoactive peptides, lysosomal proteolytic enzymes and myocardial depressant factors. Today, acute hemorrhagic pancreatitis carries a 50 to 75 % mortality. A multicenter program should be developed to standardize and evaluate forms of therapy for acute and chronic pancreatitis . More precise measurements should be obtained to delineate the pathophysiologic
1092
WORK GROUP III
Vol. 69, No . 5
abnormalities recognized in patients with longitudinal pancreatoduodenostomy, and severe acute pancreatitis. Since medical other forms of surgical therapy used in the management has consisted of " placing the treatment of acute and chronic pancreatipancreas at rest," more effective methods tis must be evaluated from both a pathoshould be developed to reduce pancreatic physiologic as well as a clinical point of metabolic and secretory activity. Perhaps view by appropriate controlled clinical tri more potent and specific drugs can be als. developed to block pancreatic stimulation Pancreatic transplantation as either total by acetylcholine or gastrointestinal hor- organ transplantation or specified cell manes. For example, the role of prosta- transplantation must be evaluated. Panglandins in pancreatic function should be creatic endocrine-exocrine insufficiency delineated. Prostaglandins stabilize lysoso- would appear to be particularly suitable for mal membranes. The causes of respiratory transplantation therapy, since pancreatitis failure in acute pancreatitis and the effects results in cell destruction with little imof pancreatic enzymes on pulmonary func- munological reaction. Unlike patients with tion should be explored. Studies should be certain forms of hepatorenal disease, redirected at determining the magnitude and cipients should tolerate pancreatic transcauses of fluid and electrolyte losses. Com- plantation with immunological complicapounds should be developed which block or tions related only to histocompatibility. inactivate pancreatic digestive enzymes in Little information is available concerning either the serum or the peritoneal cavity. It the role of dietary therapy in the treatment might be worthwhile to assess peritoneal of pancreatic disease. The pancreas of dialysis and other methods designed to animals adapts to variations in diet; thus, remove or inactivate pancreatic enzymes in a low . protein, high carbohydrate diet is the peritoneal cavity. The causes of irrever- associated with increased amylase and desible shock in acute pancreatitis are un- creased trypsin secretion, and a high proknown and demand investigation . Unfortu- tein, low carbohydrate diet is associated nately, profound shock states from any with decreased amylase and increased cause are poorly responsive to treatment · trypsin secretion. Whether the human panand often are irreversible. creas similarly adapts is not known. It has The therapy for chronic pancreatitis re- been reported that purified or elemental mains more symptomatic than definitive. diets are tolerated in patients with panThere is no detailed information concern- creatic insufficiency, but little information ing replacement therapy for chronic exo- is available concerning the effects of such crine insufficiency. Information will have diets on pancreatic function. to be developed about the preparation and The effects of acute and chronic malnuadministration of pancreatic replacement trition and starvation on pancreatic fetal therapy. development and function should be invesN umerous surgical procedures have been tigated. What growth factors or nutrients proposed for the treatment of acute and are essential for normal fetal pancreatic chronic pancreatitis. These operations development and subsequent function? have aimed at correcting the proposed or The effects of intravenous alimentation on hypothetical physiological abnormality. pancreatic function should be investigated Thus, at a time when the popular theory since deprivation of food from the gastroinsuggested bile reflux to be the cause of testinal tract in rats lowers the production pancreatitis, efforts were made to divert of gastrin, which is a growth hormone for bile away from the pancreas. At another the pancreas in that species. We do not yet time , the prevalent theory suggested due- know which gastrointestinal hormones tal obstruction, and procedures were devel- have a trophic or growth-promoting effect oped to correct or revise the ductal system. on the human pancreas. To date, surgical therapy has produced While cystic fibrosis does not solely inonly equivocal results. The value of pan- volve the pancreas, the organ is a major createctomy, subtotal pancreatectomy, target. Through developments in modern
November 1975
DISEASES OF THE PANCREAS
medical care, patients with cystic fibrosis may now live to young adulthood. Specific information should be obtained characterizing the biochemical, metabolic, and genetic abnormalities responsible for this disease. When such information is available, prevention and effective therapy may be possible.
II. Basic Research Related to the Pancreas Fundamental research, not necessarily related to identifiable diseases, deserves a high priority, for it is this form of research that permits most future clinical discoveries to be made. More definitive information is required about mechanisms controlling pancreatic regeneration and growth, pancreatic protein synthesis and secretion, and the action of gastrointestinal hormones and biogenic amines on pancreatic cell function. We need information concerning the inter-relationships between the pancreas and the stomach, between pancreatic enzymes and intestinal mucosal cells, and between the exocrine and endocrine portions of the pancreas. Although long considered a nonregerierative organ, the pancreas possesses exceptional capability for growth and regeneration. Fundamental research should be directed toward understanding control of these processes. If chronic pancreatitis is characterized by loss of pancreatic exocrine-endocrine function, then regeneration should normally be expected to repair such loss. Likewise, if gastrin and acetylcholine have trophic effects on the pancreas, then the impact of subtotal gastrectomy with antrectomy and vagotomy needs to be explored. It has been suggested that exocrine elements may undergo transition to form endocrine elements. This process, called "nesidioblastosis," needs to be defined. If such a phenomenon does occur, then islet cell dysfunction may be corrected by facilitating differentiation of exocrine elements into endocrine elements. Such a process would be of fundamental significance in the treatment of diabetes mellitus. A hormone or tissue substance may control this process. The biochemical-physiological problems
1093
involved in acinar cell secretion are relevant to the function of all secretory cells. Subcellular mechanisms concerned with synthesis and secretion have been better characterized for the pancreas than for any other exocrine gland. Many of our fundamental concepts about the biology of secretory cells have come from studies of the pancreas. These include incorporation of amino acids into secretory proteins by ribosomes on the rough endoplasmic reticulum, formation of the membranes of zymogen granules by the Golgi apparatus, the mechanism of extrusion of zymogen granules during stimulation by nerves and hormones, the duration of each of these phases, and the energy requirements for them. Information derived from these studies applies to cell biology and to cell function of other gastrointestinal organs. There is a need to apprise gastroenterologists of this work in order to identify possible applications. By the use of photoaffinity labeling, investigators have succeeded in covalently bonding peptide hormones to their receptors on pancreatic acinar cells. This should make it possible to isolate and chemically identify the receptor. This work deserves abundant support because of its pervasive importance in all aspects of biology. Although considerable research has been directed toward understanding the role that gastrointestinal hormones play in health and disease, much remains to be done. The precise mechanism of action of gastrointestinal hormones on their respective target cells has not been defined. The effects of gastrin, secretin, cholecystokinin, and of candidate hormones on biochemical and biophysical events in pancreatic acinar and ductal cells await delineation. The interaction of gastrointestinal hormones, as well as their interplay with hormones of the parathyroid, thyroid, and endocrine pancreas should be fully explored. The interaction of neural and hormonal factors in pancreatic stimulation awaits definition. There is suggestive evidence that pancreatic enzymes may have deleterious effects on intestinal mucosal cells. It has been proposed that digestive enzymes, particularly proteolytic enzymes such as tryp-
1094
Vol. 69, No . 5
WORK GROUP lii
sin and carboxypeptidase, adhere to mucosal cell borders. Under conditions of shock or hypoxia, these enzymes injure the intestinal epithelial cell. Pancreatectomized animals or animals having pancreatic secretions diverted from the small bowel tolerate conditions such as hypoxia, hemorrhagic shock, and radiation therapy better than intact animals. Some of the mortality associated with surgery, trauma, or radiation may result from this action of pancreatic enzymes on intestinal mucosa. If so, it would be appropriate in some circumstances to feed,patients material which would not stimulate usual degrees of pancreatic or proteolytic enzymes. Such maneuvers might appreciably decrease mortality and morbidity in patients undergoing major surgical procedures such as heart transplants, in patients receiving radiation or cytotoxic drugs, and in patients
in shock. Feeding inhibitors of the enzymes might also prove useful. III. Priorities Developing a multicenter program to evaluate therapy of acute pancreatitis would have the most immediate impact on national health related to diseases of the exocrine pancreas. An interdisciplinary effort should be undertaken to understand the pathophysiological mechanisms involved in pancreatitis and the complications observed in patients with the disease. A sizeable part of the resources invested in this research should be directed toward fundamental studies to provide a better understanding of pancreatic acinar and ductal cell function, inter-relationships between the pancreas and stomach, the pancreas and intestines, and control of pancreatic regeneration and growth.
List of Persons Who Contributed Statements Used in Preparing This Report Work Group Members Paul D. Webster, Chariman Marion C. Anderson Frank P. Brooks Patrick J . Fitzgerald Vay Liang W. Go James D. Jamieson
Other Contributors L. G. Bartholomew Maynard Case John B. Gross B. J . Haverback Henry Janowitz
James H. Meyer William Silen J . A. Vennes Leslie Zieve
Vol. 69, No.5 Printed in U.S .A.
WORK GROUP III
Diseases of the pancreas I. Research related to pancreatitis A. Epidemiology B. Genetics C. Pathogenesis D. Diagnosis E. Treatment II. Basic research related to the pancreas III. Priorities
The commonest diseases of the exocrine pancreas are dramatic, debilitating, and deadly: acute and chronic inf1ammation (pancreatitis) and cancer of the gland . We shall concern ourselves in this report with pancreatitis. There is undoubtedly a connection of unknown nature between alcoholism, inf1ammation of the pancreas, and cancer of the pancreas. Also, diseases of the exocrine or digestive portion of the pancreas affect the endocrine or hormoneproducing portion of the organ. But again we do not have this aspect as our major concern in this report. Epidemiological data indicate that patients with pancreatic diseases constitute a significant portion of individuals suffering from digestive disorders. Acute and chronic pancreatitis have a worldwide incidence, and in the United States the form of the disease associated with chronic alcoholism is a major health problem. The pancreas manufactures, stores, and "packages" for export into the intestinal tract the enzymes required for digestion of the major classes of foodstuffs: sugars, proteins , and fats. In acute pancreatitis it is as if this factory explodes and digestive enzymes no longer in safe "packages" attack the factory itself. We know so little about pancreatic disease because we know relatively little about how the normal pancreas works. This inadequacy results largely from the fact that research on the pancreas has lagged behind that of other digestive or-
gans. The lack of research on the pancreas may be explained in part by the erroneous notion that exocrine pancreatic diseases are uncommon, by the inaccessibility of the pancreas for clinical investigation, and by the lack of specific and rapid methods to study pancreatic function. As a result, our current diagnostic tools remain crudely qualitative, our ability to diagnose early stages of pancreatic disease is nonexistent, and the regimen of therapy and our therapeutic results have not changed over the past 3 decades . This report emphasizes the point that technical and methodological capabilities necessary for advancing knowledge of the digestive pancreas are available and that appreciable insight into pancreatic runetion and disease are within the grasp of the investigative gastroenterologist. The substance of this report is presented under two major subheadings: (I) applied research directly related to diseases of the pancreas, and (II) basic research related to understanding pancreatic function. It is our conviction that if more fundamental information were available concerning pancreatic function at the organ and cellular level it would find application in improvements in diagnosis and treatment of pancreatic disease. The subheadings dealing with diseases of the pancreas have been grouped according to etiology, pathogenesis, diagnosis, and therapy. The subheadings dealing with fundamental research are presented in a more problem-oriented
1088
November 1975
DISEASES OF THE PANCREAS
manner. We conclude with a brief summary of the present status of the field and a statement about proposed future research. I. Research Related to Pancreatitis Research should be directed toward applying available technology to studies of pancreatic diseases. The most common forms of human exocrine pancreatic disease, acute and chronic pancreatitis, probably represent a continuum of the same pathophysiological process, that is, inflammatory destruction of the pancreas leading to a loss of both exocrine and endocrine functions.
A. Epidemiology Epidemiological information about pancreatitis is limited. Available studies indicate that pancreatitis has a worldwide distribution, with considerable variation in its incidence in different parts of the world. Epidemiological studies should be conducted to identify target or index persons and to determine what characteristics predispose certain individuals or groups of individuals to the development of pancreatitis. Especially the roles of diet, alcohol, exposure to environmental pollutants, and regional factors should be weighed to identify those individuals who are at greatest risk for pancreatic disease. B. Genetics At least two forms of genetically transmitted pancreatitis are recognized. One is associated with aminoaciduria. In addition, there may be a number of related subtypes which have a metabolic etiology. A second form of hereditary pancreatitis seems to arise from structural abnormalities in the ductal system or sphincter. Further, it is likely that genetic factors play a major role in determining the predisposition of individuals to exocrine pancreatic disease. Many observations suggest a host-agent interaction and sensitivity of the host may be genetically determined. Thus, genetic differences may influence the susceptibility of the pancreas to injury from alcohol or drugs. This has been vividly demonstrated recently in the way
1089
patients with abnormalities of fat metabolism (various types of hyperlipidemia) may develop severe pancreatitis when taking birth control pills. Research should be directed toward understanding the mechanisms of inheritance of pancreatitis, as well as characterizing the molecular defect. Such studies should include cystic fibrosis of the pancreas and genetic relationships between exocrine and endocrine diseases.
C. Pathogenesis There is a curious paradox about the way in which pancreatitis develops. We know many factors which appear to trigger the attacks, yet we know very little about how they do this. These possible causative conditions include alcoholism, biliary tract disease, drugs (including diuretics), trauma, uremia, hypercalcemia, cigarette smoking, and disturbances of fat metabolism. While conditions or factors associated with pancreatitis are identifiable in many instances, the mechanisms at the cellular level have not been identified. In this country, alcoholism is the most common condition associated with pancreatitis. Over 70% of patients seen in one surgical clinic with acute or chronic pancreatitis were heavy consumers of alcohol, with no difference in incidence between sustained "heavy" drinkers and "binge" drinkers. Patients with pancreatitis who are excessive drinkers may represent a special subset of the total population of drinkers, since most alcoholics do not develop pancreatitis, and current medical experience suggests that alcoholic cirrhosis of the liver and alcoholic pancreatitis are infrequently associated. The reason for this difference is completely unknown. The most widely accepted hypothesis concerning the pathogenesis of acute pancreatitis is the autodigestion theory which proposes that proenzymes such as trypsinogen, chymotrypsinogen, or proelastase are activated within the pancreas, whereas in health they are not activated until they reach the intestine. These active enzymes then digest cellular membranes and cause
1090
WORK GROUP Ill
necrosis. Cellular injury and death results in the liberation of more injurious enzymes. There is damage of capillary basement membranes, increased capillary permeability, and engorgement of lymphatics. A cascade of injurious events ensues culminating in the development of acute hemorrhagic pancreatitis. These postulated events require validation; if they occur as described, then each event presents a potential opportunity to interrupt the cascade and stop the disease. The mechanism by which intrapancreatic activation of proenzymes occurs in pancreatitis is unknown. Pancreatic tissue and juice contain peptides that inhibit enzyme activity and enzyme activation. The structure of these inhibitors is now being elucidated. It will be important to determine whether a deficiency or abnormality of these inhibitors is a factor in the inappropriate activation of pancreatitis. Recent studies suggest that some of the enzymes concerned in blood clotting may participate in activation of pancreatic proenzymes and could be involved in the inappropriate activation seen in pancreatitis. The pancreatic enzymes often combine with specific inhibitors or with plasma proteins after they have been activated in pancreatitis. The introduction of radioimmunoassay of the pancreatic enzymes promises to make it possible to measure the proenzymes and their active forms in tissue, exudate, and blood in both normal and diseased states. Just as premature intrapancreatic activation of enzymes appears to be the central problem in acute pancreatitis, calcification of the pancreas is the central problem in chronic pancreatitis. Even when calcium deposits are not evident from X-rays, accumulation of calcium is a regular feature of chronic pancreatitis . Calcium is bound to and secreted with pancreatic enzymes, just as it is with other digestive enzymes such as salivary amylase and gastric pepsin, but the mechanisms that operate to cause accumulation of calcium carbonate in chronic pancreatitis are just beginning to be studied. Clinical studies should be undertaken to identify pathophysiologic events involved
Vol . 69, No.5
in human pancreatitis. These studies would, by necessity, be retrospective and largely descriptive. However, information derived from human studies could be applied to developing models in experimental animals. Studies using experimental animals might then define the molecular and pathophysiological events. The concept of a protective barrier at the ductal surface can be examined using morphological and ultrastructural methods. Methods can be developed to measure pancreatic intraductal pressure in patients and to determine whether increased intraductal pressure leads to escape of pancreatic enzymes and subsequent activation. Research should be directed at identifying molecular mechanisms involved in injury to pancreatic cells. The effects of steroids, tetracycline, and other drugs on the function of pancreatic acinar cells deserve investigation. Since chronic alcoholism is the most commonly recognized condition associated with pancreatitis, the effects of alcohol on the structure and function of pancreatic cells should be minutely and thoroughly defined. Does alcohol cause pancreatitis by altering lysosomal stability or does it alter metabolism in such a way as to produce cell injury? Surprisingly, despite considerable suggestive evidence that immunological factors play a role in the pathogenesis of common gastrointestinal disease~, such as ulcerative colitis, Crohn's disease, malabsorption syndromes, hepatitis, and pernicious anemia, only a little research has been devoted to this factor as a possible cause of pancreatitis . Techniques used in implicating immune factors in other disorders could be easily applied to the problem of pancreatitis. D. Diagnosis Methods employed in the diagnosis of acute and chronic pancreatitis have changed very little in the past 40 years. The diagnosis of acute pancreatitis is still based on history, physical examination, and supporting serum amylase or lipase. Serum enzymes such as trypsin , deoxyribonuclease, elastase, leucinoaminopeptidase,
November 1975
DISEASES OF THE PANCREAS
and others have been suggested to be of value in the diagnosis of pancreatic disease, but these laboratory tests have not gained broad acceptance. Pancreatic secretory function tests, although described more than 40 years ago, are presently used in only a few medical centers. Improvements in the radiological diagnosis of pancreatic disease include the use of duodenal hypotonography, pancreatic artedography, and more recently' endoscopic retrograde pancreatography; but these methods are indirect and time consuming. Pancreatic scanning techniques have been hindered by the lack of radioisotopes which specifically label the pancreas. Research directed at developing better methods for the diagnosis of acute and chronic pancreatic disease should have a high priority. A multicenter study should be established to evaluate and develop new methods for the diagnosis of acute pancreatitis. More precise knowledge should be obtained concerning factors which determine the degree and duration of serum enzyme elevations. Comparisons should also be made to determine which of the many serum enzymes are most helpful in the diagnosis of pancreatic disease. Isolation and characterization of the isozymes of pancreatic enzymes promises to greatly improve the specificity of these measurements for diagnosis. Radioimmunoassay will probably be a useful method for measurement of the individual isoenzymes. This emerging field of study deserves strong support. The technology of pancreatic secretory function tests needs standardization and simplification for widespread use in all hospital centers. Efforts should be directed at obtaining isotopically labeled compounds which concentrate specifically in the pancreas and are suitable for scanning techniques. Radiographic and arteriagraphic methods for visualizing the pancreas require improvement. For example, it has been shown recently that intra-arterial injection of a selective vasodilator, such as prostaglandin E,, into the superior mesenteric artery just prior to performing angiography of the intestinal circulation, greatly improves visualization of the mesenteric
1091
and portal veins near the head of the pancreas. The angiogram thus becomes more useful in diagnosing lesions of the pancreas which distort vascular architecture . Improvements in instrumentation for endoscopic retrograde pancreatography are also needed . Instruments should be devised which would allow visualization and biopsy of the pancreas through a peritoneoscope. The inability to diagnose exocrine pancreatic diseases at an early stage presents a major block to better recognition and management. With better instrumentation, better clinical studies of the pancreas might be obtained, analogous to the way in which needle biopsy of the liver opened up hepatology as a clinical field. New areas of pancreatic research need to be pursued through similar advances in instrumentation. The following areas offer promise. (a) Biopsy of the pancreas, either percutaneous or transduodenal; (b) endoscopic technics-better development of side-view instruments for pancreatic duct cannulation; (c) peritoneoscopy with visualization of the pancreas; (d) ultrasound and sonic procedures to identify pancreatic masses; (e) radioisotopic methods for labeling pancreatic tissue and for measuring exocrine secretion, blood flow, and enzyme syntheSIS.
E . Treatment The therapy of acute pancreatitis at present is primarily supportive and without a solid scientific basis. Recognized pathophysiologic abnormalities include: (a) hypovolemia, due in part to loss of fluid into the abdomen and retroperitoneal spaces; (b) hypoxemia, due in part to loss of lung compliance, depressed surfactin activity, and pulmonary edema; (c) irreversible shock due possibly to the release into the blood of vasoactive peptides, lysosomal proteolytic enzymes and myocardial depressant factors. Today, acute hemorrhagic pancreatitis carries a 50 to 75 % mortality. A multicenter program should be developed to standardize and evaluate forms of therapy for acute and chronic pancreatitis . More precise measurements should be obtained to delineate the pathophysiologic
1092
WORK GROUP III
Vol. 69, No . 5
abnormalities recognized in patients with longitudinal pancreatoduodenostomy, and severe acute pancreatitis. Since medical other forms of surgical therapy used in the management has consisted of " placing the treatment of acute and chronic pancreatipancreas at rest," more effective methods tis must be evaluated from both a pathoshould be developed to reduce pancreatic physiologic as well as a clinical point of metabolic and secretory activity. Perhaps view by appropriate controlled clinical tri more potent and specific drugs can be als. developed to block pancreatic stimulation Pancreatic transplantation as either total by acetylcholine or gastrointestinal hor- organ transplantation or specified cell manes. For example, the role of prosta- transplantation must be evaluated. Panglandins in pancreatic function should be creatic endocrine-exocrine insufficiency delineated. Prostaglandins stabilize lysoso- would appear to be particularly suitable for mal membranes. The causes of respiratory transplantation therapy, since pancreatitis failure in acute pancreatitis and the effects results in cell destruction with little imof pancreatic enzymes on pulmonary func- munological reaction. Unlike patients with tion should be explored. Studies should be certain forms of hepatorenal disease, redirected at determining the magnitude and cipients should tolerate pancreatic transcauses of fluid and electrolyte losses. Com- plantation with immunological complicapounds should be developed which block or tions related only to histocompatibility. inactivate pancreatic digestive enzymes in Little information is available concerning either the serum or the peritoneal cavity. It the role of dietary therapy in the treatment might be worthwhile to assess peritoneal of pancreatic disease. The pancreas of dialysis and other methods designed to animals adapts to variations in diet; thus, remove or inactivate pancreatic enzymes in a low . protein, high carbohydrate diet is the peritoneal cavity. The causes of irrever- associated with increased amylase and desible shock in acute pancreatitis are un- creased trypsin secretion, and a high proknown and demand investigation . Unfortu- tein, low carbohydrate diet is associated nately, profound shock states from any with decreased amylase and increased cause are poorly responsive to treatment · trypsin secretion. Whether the human panand often are irreversible. creas similarly adapts is not known. It has The therapy for chronic pancreatitis re- been reported that purified or elemental mains more symptomatic than definitive. diets are tolerated in patients with panThere is no detailed information concern- creatic insufficiency, but little information ing replacement therapy for chronic exo- is available concerning the effects of such crine insufficiency. Information will have diets on pancreatic function. to be developed about the preparation and The effects of acute and chronic malnuadministration of pancreatic replacement trition and starvation on pancreatic fetal therapy. development and function should be invesN umerous surgical procedures have been tigated. What growth factors or nutrients proposed for the treatment of acute and are essential for normal fetal pancreatic chronic pancreatitis. These operations development and subsequent function? have aimed at correcting the proposed or The effects of intravenous alimentation on hypothetical physiological abnormality. pancreatic function should be investigated Thus, at a time when the popular theory since deprivation of food from the gastroinsuggested bile reflux to be the cause of testinal tract in rats lowers the production pancreatitis, efforts were made to divert of gastrin, which is a growth hormone for bile away from the pancreas. At another the pancreas in that species. We do not yet time , the prevalent theory suggested due- know which gastrointestinal hormones tal obstruction, and procedures were devel- have a trophic or growth-promoting effect oped to correct or revise the ductal system. on the human pancreas. To date, surgical therapy has produced While cystic fibrosis does not solely inonly equivocal results. The value of pan- volve the pancreas, the organ is a major createctomy, subtotal pancreatectomy, target. Through developments in modern
November 1975
DISEASES OF THE PANCREAS
medical care, patients with cystic fibrosis may now live to young adulthood. Specific information should be obtained characterizing the biochemical, metabolic, and genetic abnormalities responsible for this disease. When such information is available, prevention and effective therapy may be possible.
II. Basic Research Related to the Pancreas Fundamental research, not necessarily related to identifiable diseases, deserves a high priority, for it is this form of research that permits most future clinical discoveries to be made. More definitive information is required about mechanisms controlling pancreatic regeneration and growth, pancreatic protein synthesis and secretion, and the action of gastrointestinal hormones and biogenic amines on pancreatic cell function. We need information concerning the inter-relationships between the pancreas and the stomach, between pancreatic enzymes and intestinal mucosal cells, and between the exocrine and endocrine portions of the pancreas. Although long considered a nonregerierative organ, the pancreas possesses exceptional capability for growth and regeneration. Fundamental research should be directed toward understanding control of these processes. If chronic pancreatitis is characterized by loss of pancreatic exocrine-endocrine function, then regeneration should normally be expected to repair such loss. Likewise, if gastrin and acetylcholine have trophic effects on the pancreas, then the impact of subtotal gastrectomy with antrectomy and vagotomy needs to be explored. It has been suggested that exocrine elements may undergo transition to form endocrine elements. This process, called "nesidioblastosis," needs to be defined. If such a phenomenon does occur, then islet cell dysfunction may be corrected by facilitating differentiation of exocrine elements into endocrine elements. Such a process would be of fundamental significance in the treatment of diabetes mellitus. A hormone or tissue substance may control this process. The biochemical-physiological problems
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involved in acinar cell secretion are relevant to the function of all secretory cells. Subcellular mechanisms concerned with synthesis and secretion have been better characterized for the pancreas than for any other exocrine gland. Many of our fundamental concepts about the biology of secretory cells have come from studies of the pancreas. These include incorporation of amino acids into secretory proteins by ribosomes on the rough endoplasmic reticulum, formation of the membranes of zymogen granules by the Golgi apparatus, the mechanism of extrusion of zymogen granules during stimulation by nerves and hormones, the duration of each of these phases, and the energy requirements for them. Information derived from these studies applies to cell biology and to cell function of other gastrointestinal organs. There is a need to apprise gastroenterologists of this work in order to identify possible applications. By the use of photoaffinity labeling, investigators have succeeded in covalently bonding peptide hormones to their receptors on pancreatic acinar cells. This should make it possible to isolate and chemically identify the receptor. This work deserves abundant support because of its pervasive importance in all aspects of biology. Although considerable research has been directed toward understanding the role that gastrointestinal hormones play in health and disease, much remains to be done. The precise mechanism of action of gastrointestinal hormones on their respective target cells has not been defined. The effects of gastrin, secretin, cholecystokinin, and of candidate hormones on biochemical and biophysical events in pancreatic acinar and ductal cells await delineation. The interaction of gastrointestinal hormones, as well as their interplay with hormones of the parathyroid, thyroid, and endocrine pancreas should be fully explored. The interaction of neural and hormonal factors in pancreatic stimulation awaits definition. There is suggestive evidence that pancreatic enzymes may have deleterious effects on intestinal mucosal cells. It has been proposed that digestive enzymes, particularly proteolytic enzymes such as tryp-
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WORK GROUP lii
sin and carboxypeptidase, adhere to mucosal cell borders. Under conditions of shock or hypoxia, these enzymes injure the intestinal epithelial cell. Pancreatectomized animals or animals having pancreatic secretions diverted from the small bowel tolerate conditions such as hypoxia, hemorrhagic shock, and radiation therapy better than intact animals. Some of the mortality associated with surgery, trauma, or radiation may result from this action of pancreatic enzymes on intestinal mucosa. If so, it would be appropriate in some circumstances to feed,patients material which would not stimulate usual degrees of pancreatic or proteolytic enzymes. Such maneuvers might appreciably decrease mortality and morbidity in patients undergoing major surgical procedures such as heart transplants, in patients receiving radiation or cytotoxic drugs, and in patients
in shock. Feeding inhibitors of the enzymes might also prove useful. III. Priorities Developing a multicenter program to evaluate therapy of acute pancreatitis would have the most immediate impact on national health related to diseases of the exocrine pancreas. An interdisciplinary effort should be undertaken to understand the pathophysiological mechanisms involved in pancreatitis and the complications observed in patients with the disease. A sizeable part of the resources invested in this research should be directed toward fundamental studies to provide a better understanding of pancreatic acinar and ductal cell function, inter-relationships between the pancreas and stomach, the pancreas and intestines, and control of pancreatic regeneration and growth.
List of Persons Who Contributed Statements Used in Preparing This Report Work Group Members Paul D. Webster, Chariman Marion C. Anderson Frank P. Brooks Patrick J . Fitzgerald Vay Liang W. Go James D. Jamieson
Other Contributors L. G. Bartholomew Maynard Case John B. Gross B. J . Haverback Henry Janowitz
James H. Meyer William Silen J . A. Vennes Leslie Zieve