- Email: [email protected]
Digestive Disease as a National Problem
Vol. 55, No.3 Printed in U.S.A.
GASTROENTEROLOGY
Copyright © 1968 by The Williams & Wilkins Co.
DIGESTIVE DISEASE AS A NATIONAL PROBLEM VII. The state of our knowledge of representative diseases
PEPTIC ULCER MoRTON
I.
GRossMAN
About 4 million persons in the United States have peptic ulcers. The cost of medical care and loss of earning power due to ulcer disease is about 1 billion dollars per year. Peptic ulcers occur in areas bathed by acid and pepsin secreted by the stomach. Ulcer formation requires acid; no acid, no ulcer. Increased acid secretion is one cause of ulcer, but most patients with ulcer do not secrete abnormally large amounts of acid. Since ulcers cannot persist without acid, decrease in acid should be therapeutically helpful in all patients with this disease. Since there are failures of treatment based on reduction of acid both by medical and surgical means, our methods for controlling acid obviously need improvement. Since most patients with ulcer do not secrete excessive amounts of acid, they must have impaired defense against acid. There are probably many genetic and environmental factors that contribute to defense against acid but we know little about their nature and almost nothing about measuring them quantitatively. Two genetic factors associated with ulcer are blood group 0 and failure to secrete blood group substance in saliva. These factors are weak determinants; together These are abstracts of talks given at a Conference on Digestive Disease as a National Problem sponsored jointly by The American Gastroenterological Association, The Digestive Disease Foundation, and the National Institute of Arthritis and Metabolic Diseases. Other portions of this Conference have been reported in previous issues of this journal. Address requests for reprints to: Dr. M. I. Grossman, Veterans Administration Center, Los Angeles, California 90073. 392
they account for less than 3% of the variability in occurrence of ulcer. Environmental factors that have been suspected of contributing to ulcer disease are psychological stress, smoking, and use of aspirin. There are unquestionably others yet to be identified. None of the suspected factors has been proved to be implicated and for none of them has a mechanism of action been unequivocally established. Research on ulcer should move in three paths. First, basic science studies on topics such as the chemical structure of gastrin and related substances should be strongly augmented. Second, epidemiological and population studies should be done to identify environmental factors such as smoking and the use of aspirin as possible contributors. Third, scientifically planned clinical trials should be conducted to determine whether the drugs and surgical operations we now use are effective and how they may be optimally employed. ULCERATIVE COLITIS JOSEPH
B.
KIRSNER
Ulcerative colitis is a chronic inflammatory disease of the large bowel. It is characterized by diffuse ulcerations, at times by a pseudopolypoid, granulation tissue type of reaction or by a necrotizing process, vvith slough of the mucosa and submucosa. JVIany etiological concepts have been suggested, but without conclusive supporting evidence. Information as to the possible role of bacteria or viruses and of bacterial endotoxins is scanty. Psychogenic disturbances contribute to the course of the disease, and perhaps also to its origin, but the mechanism is obscure. The possibility of an immunological pathogenesis has attracted particular attention in recent years, but fundamental knowledge of this problem only now is being accumulated.
September 1968
DIGESTIVE DISEASE. VII
Ulcerative colitis limited to the rectum (proctitis) appears to be a variant of the disease, but its course is much milder. A regional enteritis type of process may involve the colon ("Crohn's disease of the colon," "granulomatous colitis"), but its relationship to "ordinary" ulcerative colitis is not known. The course of ulcerative colitis tends to be chronic, recurrent, and complicated. Many patients respond to medical treatment and striking reversibility of the colonic disease is noted occasionally. In ot her patients, the disease becomes progressively worse culminating in total colectomy and ileostomy in 15 to 20% of cases. The general incidence of ulcerative colitis and other inflammatory bowel diseases remains unknown, but appears to be increasing. In our experience, the number of new cases annually has increased 10fold, and a similar trend has been noted in other major medical centers. The morbidity of ulcerative colitis is very high. The mortality rate is comparatively small but significant. Among the contributing factors are complications such as carcinoma of the colon, perforation, peritonitis and massive hemorrhage, and a variety of systemic complications including liver disease, nephrolithiasis, malnutrition, and growth retardation among children. Hospitalizations often are prolonged. The financial cost to the patient and to the family is enormous. The emotional cost to the patient and to the family is incalculable. The challenge presented by ulcerative colitis, regional enteritis, and granulomatous colitis is significant and intriguing. Yet relatively little organized research is in progress. National Institutes of Health support for such research is extremely limited. The National Science Foundation provides no support. There is urgent need to study virtually every phase of ulcerative colitis and the other inflammatory bowel diseases: epidemiology, family occurrences, ethnic relationships, psychogenic and sociologic aspects, etc.; the nature of the tissue reaction; and the process of injury and healing in the colon. Since the incidence of colon cancer is greatly in-
393
creased in ulcerative colitis, these patients present an unusual opportunity for the investigation of a significant cancer problem. There is need also to study the funda mental functions of the colon and its cellular components, including transport mechanisms, protein synthesis, and a variety of related problems. The occurrence of intestinal diseases among animals, such as granulomatous colitis in Boxer dogs, offers a potentially fruitful area of cooperative study with veterinarians. Thus, comprehensive investigation of inflammatory bo;vel disease presents an unusually favorable opportunity to unravel important biomedical problems related not only to the colon but also to the total human orgamsm. HEPATITIS THOMAS C. CHALMERS
Viral hepatitis is the most common infectious disease for which no etiological agent has ever been isolated. There are hundreds of thousands of cases in America each year. Between 2000 and 5000 die yearly of the disease. Epidemiological studies suggest a mode of transmission in approximately 50% of cases of the infectious or orally transmitted disease. It should be possible, with sufficient funds and more efficient dissemination of information, to prevent these. A particularly lethal form occurs after approximately 1% of blood transfusion episodes. Twelve per cent of these patients die. Better selection of blood donors could prevent some of these, but more effective tests are needed to detect the carrier of the virus. The efficacy of y-globulin in preYenting the disease still needs to be properly evaluated. There is no specific treatment of the acute disease. Current information on t he relationship of viral hepatitis to nonalcoholic cirrhosis is either conflicting or unreliable. Most of the above problems \vould be solved by the discovery of the Yirus and successful preparation of a vaccine. Some progress is being made in this area.
DIGESTIVE DISEASE. VII
394
It is difficult to understand how hepatitis research has received so little support in the past. The partial or complete resolution of most other infectious disease problems leaves it as a shining example of a desperate public health need.
ALCOHOLIC LIVER DISEASE G.
Vol. 55, No.3
urgent need of further study include the fundamental mechanisms underlying the development of hepatic coma, hepatorenal failure, and bleeding esophageal varices, and a more critical appraisal of and new search for agents that may stimulate hepatic regeneration, reverse hepatocellular degenerative changes, or suppress the inflammatory reaction in cirrhosis.
KLATSKIN
Although the over-all death rate in the United States has declined progressively over the past 60 years, there has been a steady increase in the number of deaths from cirrhosis, a disease which now ranks among the more important causes of death in this country. Available evidence indicates that this trend is attributable to an increase in alcohol consumption. The evidence shows: (1) that, while the incidence of alcoholic cirrhosis has risen, the life-span of patients with this disease has increased remarkably over the past 3 decades; {2) that this improvement in prognosis is in a large measure attributable to recognition that the disease is not necessarily progressive, that complications of the disease play an important role in morbidity and mortality, and that current methods of managing these are more effective than in the past; and {3) that cessation of alcohol consumption is the most important single factor that leads to recovery. The fundamental problem of how chronic alcoholism leads to cirrhosis remains unresolved, and requires further study. From animal experiments it is clear that both alcohol itself and malnutrition may affect the liver, but the relevance of these observations to the pathogenesis of Laennec's cirrhosis in man has not been established. Since feeding alcohol to animals never gives rise to cirrhosis, and since the disease occurs in only a small fraction of human subjects who drink to excess, constitutional factors, possibly under genetic control, may play an important role. This aspect of the problem merits careful investigation. Equally important problems that are in
DIARRHEAL DISEASE RoBERT
S.
GoRDON, JR.
Although cholera and other diarrheal diseases are not important public health problems in the United States, they are major causes of death in many parts of the world with which we are concerned. During the last decade cholera, particularly, has spread from its former very limited area in Bengal to cover most of south Asia from the Philippines to Iran. Since 1958, when United States government agencies began seriously to carry out and support research on cholera, a number of important facts have been conclusively proven. Cholera kills only by producing depletion of water and electrolytes; it is otherwise a self-limited disease of short duration. The death rate can be reduced to a negligible figure by adequate intravenous replacement therapy. Antibacterial drugs shorten the course of the illness, with consequent savings in the cost of treatment. Cholera vaccine, prepared from killed whole organisms, has been in use since the last century, but only recently has its protective effect been clearly defined in controlled field trials. In the first study it reduced the attack rate 4-fold. Subsequent work has shown that the effect is transient, and largely disappears within 1 year. We still know little about the mechanism of production of diarrhea in cholera. The recent demonstration that an active toxin, capable of reproducing cholera in experimental animals, can be produced in vitro, opens new possibilities for the investigation, not only of cholera and its management, but also of the physiology and pathophysiology of the small intestine.
September 1968
DIGESTIVE DISEASE. VII
GALLSTONES FRANZ
J.
INGELFINGER
Gallstones are very common. In persons aged 5? .to 64, t he decade of greatest productivity for many, 10% of men and 20% of women in the United States and Europe have gallstones. In t he entire United States population, some 15,000,000 must possess t hese stones; nor are gallstones related to poverty, malnutrition, or lack of accomplishment. Four of our last five presidents have had gallstones. In spite of this excessive prevalence of g~ llstones, little is being done about this di~ease ,. except for improving the surgical skill With which t hese stones can be removed after they have formed, and often after they have caused acute inflammation of the gall bladder or even more serious complications. The amount of effort and money spent studyin g gallstones is infinitesimal if compared to what is spent in the study of cystic fibrosis of the pancreas or certain neuromuscular diseases which although serious, affect less than 1% of th~ number affli cted with gallstones. Modern physicochemical resources are such that the mechanisms which cause stones to form in gall bladder bile could be readily analyzed if t here were enough people properly trained and laboratories properly equipped. Current ly, in the United States, there may be five such laboratories but in view of the prevalence of these dis~ eases, vvhy not 30 or 40? The Swedes with a population one-twenty-fifth of ours are doin g twice as much as we are in determining why gallstones form. It is quite evident that some populations have many ga llstones and others nry few. In American Indians, for example, t he frequency of gallstones is excessive but studies of t his freq uency and its causes have just recently been initiated. Surgeons are very skilled in removing ga llstones and gall bladders, but it also costs a great deal of money. In view of the contagious alarm with which increasing costs of medical care are being viewed, it would seem appropriate to spend a few
395
dollars (relatively) to find out why gallstones form. Once this is known methods for their prevention become po~sible. In short, effort and dollars spent in support of research on gallstone formation should not only relieve the patient's suffering but also some of our economic woes. MALABSORPTION MARVI N H . S LEISENGER
The importance of the study of diseases characterized by malabsorption lies not so much in their mortality (exclusive of ~ntestin ~l . cancers, particularly lymphoma) m the Umted States, as in the opportunities offered for acquiring needed information. The follo·wing are areas in which intensive investigation is needed: (1) the effects of food constituents on gut stru cture and funct ion, (2) t he relationship between villous atrophy and malignancy, (3) t he role of the gut in immunological defen se mechanisms with particular reference to synthesis of I gA and IgG, (4) t he common denominators of a variety of facto rs which lead to villous a.trophy by altering t he pattern of replicatiOn by the progenitor crypt cells, and (5) the role-physiological as well as pathophysiological-of intestinal microorganisms. The story of the relationship of gluten to adult celiac disease serves to emphasize the success of collaboration between different s?ientific disciplines in clinical investigatiOn of gastrointestinal disease. An increasing number of individuals in all areasbiochemistry, nutrit ion, clinical medicine etc.-will be required to solve the problem~ posed by those gastrointestinal diseases which cause significant morbidity and mortality. CANCER OF THE COLON GEORGE
A.
HALLENBECK
About 15% of malignant t umors in man originate in the colon and rectum, and these cancers currently kill more t han 40,000 people annually in t he United States. Their detection, now as for 50 years, depends upon the examining finger, the
396
DIGESTIVE DISEASE. VII
sigmoidoscope, and the X-ray machine. In contrast with some other malignant tumors, cancers of the colon are frequently detected and removed before distant metastases have occurred, in which case 5year survival rates of 70% have been reported, a value much better than the figure of 25% that results if all cases are included. Probably improvement in diagnostic methods would be rewarding here. Extensions of efforts to develop flexible fibrooptic sigmoidoscopes and to adapt cytological techniques to the colon come to mind. Many clinical practices related to colorectal carcinoma are based on qualitative rather than quantitative data and would be improved by controlled prospective studies. For example, do pedunculated colonic polyps have enough malignant potential that they should always be removed, even if laparotomy is required? How can one decide rationally whether or when the colon of a patient who has ulcerative colitis should be removed if the question is one of potential malignant change? Does roentgen therapy for colonic cancers, given preoperatively or postoperatively, alter survival rates? In the form of familial polyposis of the colon, nature has provided a beautiful experimental model by providing colonic mucosa that will always undergo malignant change if only enough time elapses. Studies
Vol. 55, No. 3
of the biological characteristics of this mucosa compared with that of individuals who do not have the inherited defect could be revealing. Incidences of colorectal cancer vary widely over the world, and there is evidence that in people who migrate from one area to another the incidence tends gradually to approach that of the host country. Environmental conditions evidently are involved in the pathogenesis of these lesions, and perhaps play a more important role in the ordinary case than do genetic factors. The slow and difficult work of identifying such carcinogens and searching for them in the diet deserves support. Whatever the presumed carcinogenic agents may be, their mode of action is not known. Tumors and surrounding mucosa of human subjects are available for study, as are several model systems in animals that develop colonic neoplasms upon being fed specific carcinogens. One can conclude that colorectal cancer presents a significant socioeconomic problem in our country and in the world, that considerable evidence supports the concept that the incidence of the disease depends at least in part upon environmental conditions, that more vigorous study of the behavior, etiology, and pathogenesis of these tumors is needed, and that avenues to approach the problem exist.
GASTROENTEROLOGY
Copyright © 1968 by The Williams & Wilkins Co.
DIGESTIVE DISEASE AS A NATIONAL PROBLEM VII. The state of our knowledge of representative diseases
PEPTIC ULCER MoRTON
I.
GRossMAN
About 4 million persons in the United States have peptic ulcers. The cost of medical care and loss of earning power due to ulcer disease is about 1 billion dollars per year. Peptic ulcers occur in areas bathed by acid and pepsin secreted by the stomach. Ulcer formation requires acid; no acid, no ulcer. Increased acid secretion is one cause of ulcer, but most patients with ulcer do not secrete abnormally large amounts of acid. Since ulcers cannot persist without acid, decrease in acid should be therapeutically helpful in all patients with this disease. Since there are failures of treatment based on reduction of acid both by medical and surgical means, our methods for controlling acid obviously need improvement. Since most patients with ulcer do not secrete excessive amounts of acid, they must have impaired defense against acid. There are probably many genetic and environmental factors that contribute to defense against acid but we know little about their nature and almost nothing about measuring them quantitatively. Two genetic factors associated with ulcer are blood group 0 and failure to secrete blood group substance in saliva. These factors are weak determinants; together These are abstracts of talks given at a Conference on Digestive Disease as a National Problem sponsored jointly by The American Gastroenterological Association, The Digestive Disease Foundation, and the National Institute of Arthritis and Metabolic Diseases. Other portions of this Conference have been reported in previous issues of this journal. Address requests for reprints to: Dr. M. I. Grossman, Veterans Administration Center, Los Angeles, California 90073. 392
they account for less than 3% of the variability in occurrence of ulcer. Environmental factors that have been suspected of contributing to ulcer disease are psychological stress, smoking, and use of aspirin. There are unquestionably others yet to be identified. None of the suspected factors has been proved to be implicated and for none of them has a mechanism of action been unequivocally established. Research on ulcer should move in three paths. First, basic science studies on topics such as the chemical structure of gastrin and related substances should be strongly augmented. Second, epidemiological and population studies should be done to identify environmental factors such as smoking and the use of aspirin as possible contributors. Third, scientifically planned clinical trials should be conducted to determine whether the drugs and surgical operations we now use are effective and how they may be optimally employed. ULCERATIVE COLITIS JOSEPH
B.
KIRSNER
Ulcerative colitis is a chronic inflammatory disease of the large bowel. It is characterized by diffuse ulcerations, at times by a pseudopolypoid, granulation tissue type of reaction or by a necrotizing process, vvith slough of the mucosa and submucosa. JVIany etiological concepts have been suggested, but without conclusive supporting evidence. Information as to the possible role of bacteria or viruses and of bacterial endotoxins is scanty. Psychogenic disturbances contribute to the course of the disease, and perhaps also to its origin, but the mechanism is obscure. The possibility of an immunological pathogenesis has attracted particular attention in recent years, but fundamental knowledge of this problem only now is being accumulated.
September 1968
DIGESTIVE DISEASE. VII
Ulcerative colitis limited to the rectum (proctitis) appears to be a variant of the disease, but its course is much milder. A regional enteritis type of process may involve the colon ("Crohn's disease of the colon," "granulomatous colitis"), but its relationship to "ordinary" ulcerative colitis is not known. The course of ulcerative colitis tends to be chronic, recurrent, and complicated. Many patients respond to medical treatment and striking reversibility of the colonic disease is noted occasionally. In ot her patients, the disease becomes progressively worse culminating in total colectomy and ileostomy in 15 to 20% of cases. The general incidence of ulcerative colitis and other inflammatory bowel diseases remains unknown, but appears to be increasing. In our experience, the number of new cases annually has increased 10fold, and a similar trend has been noted in other major medical centers. The morbidity of ulcerative colitis is very high. The mortality rate is comparatively small but significant. Among the contributing factors are complications such as carcinoma of the colon, perforation, peritonitis and massive hemorrhage, and a variety of systemic complications including liver disease, nephrolithiasis, malnutrition, and growth retardation among children. Hospitalizations often are prolonged. The financial cost to the patient and to the family is enormous. The emotional cost to the patient and to the family is incalculable. The challenge presented by ulcerative colitis, regional enteritis, and granulomatous colitis is significant and intriguing. Yet relatively little organized research is in progress. National Institutes of Health support for such research is extremely limited. The National Science Foundation provides no support. There is urgent need to study virtually every phase of ulcerative colitis and the other inflammatory bowel diseases: epidemiology, family occurrences, ethnic relationships, psychogenic and sociologic aspects, etc.; the nature of the tissue reaction; and the process of injury and healing in the colon. Since the incidence of colon cancer is greatly in-
393
creased in ulcerative colitis, these patients present an unusual opportunity for the investigation of a significant cancer problem. There is need also to study the funda mental functions of the colon and its cellular components, including transport mechanisms, protein synthesis, and a variety of related problems. The occurrence of intestinal diseases among animals, such as granulomatous colitis in Boxer dogs, offers a potentially fruitful area of cooperative study with veterinarians. Thus, comprehensive investigation of inflammatory bo;vel disease presents an unusually favorable opportunity to unravel important biomedical problems related not only to the colon but also to the total human orgamsm. HEPATITIS THOMAS C. CHALMERS
Viral hepatitis is the most common infectious disease for which no etiological agent has ever been isolated. There are hundreds of thousands of cases in America each year. Between 2000 and 5000 die yearly of the disease. Epidemiological studies suggest a mode of transmission in approximately 50% of cases of the infectious or orally transmitted disease. It should be possible, with sufficient funds and more efficient dissemination of information, to prevent these. A particularly lethal form occurs after approximately 1% of blood transfusion episodes. Twelve per cent of these patients die. Better selection of blood donors could prevent some of these, but more effective tests are needed to detect the carrier of the virus. The efficacy of y-globulin in preYenting the disease still needs to be properly evaluated. There is no specific treatment of the acute disease. Current information on t he relationship of viral hepatitis to nonalcoholic cirrhosis is either conflicting or unreliable. Most of the above problems \vould be solved by the discovery of the Yirus and successful preparation of a vaccine. Some progress is being made in this area.
DIGESTIVE DISEASE. VII
394
It is difficult to understand how hepatitis research has received so little support in the past. The partial or complete resolution of most other infectious disease problems leaves it as a shining example of a desperate public health need.
ALCOHOLIC LIVER DISEASE G.
Vol. 55, No.3
urgent need of further study include the fundamental mechanisms underlying the development of hepatic coma, hepatorenal failure, and bleeding esophageal varices, and a more critical appraisal of and new search for agents that may stimulate hepatic regeneration, reverse hepatocellular degenerative changes, or suppress the inflammatory reaction in cirrhosis.
KLATSKIN
Although the over-all death rate in the United States has declined progressively over the past 60 years, there has been a steady increase in the number of deaths from cirrhosis, a disease which now ranks among the more important causes of death in this country. Available evidence indicates that this trend is attributable to an increase in alcohol consumption. The evidence shows: (1) that, while the incidence of alcoholic cirrhosis has risen, the life-span of patients with this disease has increased remarkably over the past 3 decades; {2) that this improvement in prognosis is in a large measure attributable to recognition that the disease is not necessarily progressive, that complications of the disease play an important role in morbidity and mortality, and that current methods of managing these are more effective than in the past; and {3) that cessation of alcohol consumption is the most important single factor that leads to recovery. The fundamental problem of how chronic alcoholism leads to cirrhosis remains unresolved, and requires further study. From animal experiments it is clear that both alcohol itself and malnutrition may affect the liver, but the relevance of these observations to the pathogenesis of Laennec's cirrhosis in man has not been established. Since feeding alcohol to animals never gives rise to cirrhosis, and since the disease occurs in only a small fraction of human subjects who drink to excess, constitutional factors, possibly under genetic control, may play an important role. This aspect of the problem merits careful investigation. Equally important problems that are in
DIARRHEAL DISEASE RoBERT
S.
GoRDON, JR.
Although cholera and other diarrheal diseases are not important public health problems in the United States, they are major causes of death in many parts of the world with which we are concerned. During the last decade cholera, particularly, has spread from its former very limited area in Bengal to cover most of south Asia from the Philippines to Iran. Since 1958, when United States government agencies began seriously to carry out and support research on cholera, a number of important facts have been conclusively proven. Cholera kills only by producing depletion of water and electrolytes; it is otherwise a self-limited disease of short duration. The death rate can be reduced to a negligible figure by adequate intravenous replacement therapy. Antibacterial drugs shorten the course of the illness, with consequent savings in the cost of treatment. Cholera vaccine, prepared from killed whole organisms, has been in use since the last century, but only recently has its protective effect been clearly defined in controlled field trials. In the first study it reduced the attack rate 4-fold. Subsequent work has shown that the effect is transient, and largely disappears within 1 year. We still know little about the mechanism of production of diarrhea in cholera. The recent demonstration that an active toxin, capable of reproducing cholera in experimental animals, can be produced in vitro, opens new possibilities for the investigation, not only of cholera and its management, but also of the physiology and pathophysiology of the small intestine.
September 1968
DIGESTIVE DISEASE. VII
GALLSTONES FRANZ
J.
INGELFINGER
Gallstones are very common. In persons aged 5? .to 64, t he decade of greatest productivity for many, 10% of men and 20% of women in the United States and Europe have gallstones. In t he entire United States population, some 15,000,000 must possess t hese stones; nor are gallstones related to poverty, malnutrition, or lack of accomplishment. Four of our last five presidents have had gallstones. In spite of this excessive prevalence of g~ llstones, little is being done about this di~ease ,. except for improving the surgical skill With which t hese stones can be removed after they have formed, and often after they have caused acute inflammation of the gall bladder or even more serious complications. The amount of effort and money spent studyin g gallstones is infinitesimal if compared to what is spent in the study of cystic fibrosis of the pancreas or certain neuromuscular diseases which although serious, affect less than 1% of th~ number affli cted with gallstones. Modern physicochemical resources are such that the mechanisms which cause stones to form in gall bladder bile could be readily analyzed if t here were enough people properly trained and laboratories properly equipped. Current ly, in the United States, there may be five such laboratories but in view of the prevalence of these dis~ eases, vvhy not 30 or 40? The Swedes with a population one-twenty-fifth of ours are doin g twice as much as we are in determining why gallstones form. It is quite evident that some populations have many ga llstones and others nry few. In American Indians, for example, t he frequency of gallstones is excessive but studies of t his freq uency and its causes have just recently been initiated. Surgeons are very skilled in removing ga llstones and gall bladders, but it also costs a great deal of money. In view of the contagious alarm with which increasing costs of medical care are being viewed, it would seem appropriate to spend a few
395
dollars (relatively) to find out why gallstones form. Once this is known methods for their prevention become po~sible. In short, effort and dollars spent in support of research on gallstone formation should not only relieve the patient's suffering but also some of our economic woes. MALABSORPTION MARVI N H . S LEISENGER
The importance of the study of diseases characterized by malabsorption lies not so much in their mortality (exclusive of ~ntestin ~l . cancers, particularly lymphoma) m the Umted States, as in the opportunities offered for acquiring needed information. The follo·wing are areas in which intensive investigation is needed: (1) the effects of food constituents on gut stru cture and funct ion, (2) t he relationship between villous atrophy and malignancy, (3) t he role of the gut in immunological defen se mechanisms with particular reference to synthesis of I gA and IgG, (4) t he common denominators of a variety of facto rs which lead to villous a.trophy by altering t he pattern of replicatiOn by the progenitor crypt cells, and (5) the role-physiological as well as pathophysiological-of intestinal microorganisms. The story of the relationship of gluten to adult celiac disease serves to emphasize the success of collaboration between different s?ientific disciplines in clinical investigatiOn of gastrointestinal disease. An increasing number of individuals in all areasbiochemistry, nutrit ion, clinical medicine etc.-will be required to solve the problem~ posed by those gastrointestinal diseases which cause significant morbidity and mortality. CANCER OF THE COLON GEORGE
A.
HALLENBECK
About 15% of malignant t umors in man originate in the colon and rectum, and these cancers currently kill more t han 40,000 people annually in t he United States. Their detection, now as for 50 years, depends upon the examining finger, the
396
DIGESTIVE DISEASE. VII
sigmoidoscope, and the X-ray machine. In contrast with some other malignant tumors, cancers of the colon are frequently detected and removed before distant metastases have occurred, in which case 5year survival rates of 70% have been reported, a value much better than the figure of 25% that results if all cases are included. Probably improvement in diagnostic methods would be rewarding here. Extensions of efforts to develop flexible fibrooptic sigmoidoscopes and to adapt cytological techniques to the colon come to mind. Many clinical practices related to colorectal carcinoma are based on qualitative rather than quantitative data and would be improved by controlled prospective studies. For example, do pedunculated colonic polyps have enough malignant potential that they should always be removed, even if laparotomy is required? How can one decide rationally whether or when the colon of a patient who has ulcerative colitis should be removed if the question is one of potential malignant change? Does roentgen therapy for colonic cancers, given preoperatively or postoperatively, alter survival rates? In the form of familial polyposis of the colon, nature has provided a beautiful experimental model by providing colonic mucosa that will always undergo malignant change if only enough time elapses. Studies
Vol. 55, No. 3
of the biological characteristics of this mucosa compared with that of individuals who do not have the inherited defect could be revealing. Incidences of colorectal cancer vary widely over the world, and there is evidence that in people who migrate from one area to another the incidence tends gradually to approach that of the host country. Environmental conditions evidently are involved in the pathogenesis of these lesions, and perhaps play a more important role in the ordinary case than do genetic factors. The slow and difficult work of identifying such carcinogens and searching for them in the diet deserves support. Whatever the presumed carcinogenic agents may be, their mode of action is not known. Tumors and surrounding mucosa of human subjects are available for study, as are several model systems in animals that develop colonic neoplasms upon being fed specific carcinogens. One can conclude that colorectal cancer presents a significant socioeconomic problem in our country and in the world, that considerable evidence supports the concept that the incidence of the disease depends at least in part upon environmental conditions, that more vigorous study of the behavior, etiology, and pathogenesis of these tumors is needed, and that avenues to approach the problem exist.