- Email: [email protected]
Bile, eicosanoids, and colonic cell proliferation
August 1985
SELECTED
Comment. It is all too infrequent that a simple measure dramatically improves the outcome in debilitating inherited diseases. Now and then, such things do happen. To mention two diseases of interest to gastroenterologists, oral zinc sulfate “cures” patients with acrodermatitis enteropathica, with complete resolution of their severe diarrhea and cutaneous manifestations; vitamin E taken orally prevents the neuromuscular and retinal degeneration of abetalipoproteinemia. The paper by Chen et al. is an important advance in managing patients with type I GSD; it is even better than the continuous nocturnal feeding regime. Severe growth failure, metabolic acidosis, and recurrent hypoglycemia attacks of type I GSD responded poorly to older regimes restricting non-glucose-containing sugars requiring frequent feedings day and night. Following the observations that “bypassing” the liver via portacaval shunting (Ann Surg 1973:178:525-39) or total parenteral nutrition (Surgery 1972;72:306-14) improves most metabolic and clinical anomalies of type I GSD, Green and continuous colleagues (N Engl J Med 1976;294:423-5) introduced nocturnal intragastric clinical and metabolic
feeding. The improvements
marked overall growth and with the nocturnal feeding
regime allowed for wide patient acceptance despite the inconvenience of nightly passage of a nasogastric tube and 12-h connection to a feeding pump. With this regime, patients were further dependent on frequent (every 3 h) daytime snacks or meals. The cornstarch regime does away with the inconveniences and the risks of the tube-feeding regime. Moreover, although not discussed by the authors in the paper under review, patients themselves (and their parents) welcome the cornstarch regime as a major improvement. Our patients in Jerusalem who now follow the cornstarch regime have impressively stable normal blood glucose levels day and night, with little fluctuations after meals or exercise. More important, they feel much better. Continuous normoglycemia with low lactate levels probably helps, but the children are more impressed by being able to eat when they feel like eating, and not by the clock; by eating regular meals with the rest of the family; and by having the choice of varying amounts and types of foods like normal children. (Nonglucose sugars are still restricted, and overall caloric intake and distribution are maintained.) The patients, who were previously well controlled on the continuous nocturnal feeding regime, are themselves surprised by the improvement in mood and well-being since switching to cornstarch therapy. The need to wake up at midnight is a minor inconvenience relative and 6 AM to drink the cornstarch to the other benefits gained by this treatment modality. Similar to the experience of the authors, our youngest patient was unable to sustain normoglycemia for more than 4 h on the cornstarch regime. At 2.5 yr of age, he should have adult levels of pancreatic amylase activity, raising the question that factors other than low amylase activity may be responsible for the poor response to cornstarch in very young patients. Presumably, the success of therapy depends on slow digestion of the uncooked cornstarch, with continuous release and absorption of glucose. Our own first attempts at the cornstarch regime, using locally produced cornflour or cornstarch, were unsuccessful. Only after obtaining the same brand of cornstarch used by the authors were we successful in implementing the regime. This observation, combined with the authors’ observation that hot water or addition of lemonade renders the cornstarch ineffective, suggests that processes used by industry in producing raw cornstarch are important as to whether a particular brand will be effective or not. One might predict that such a simple method for maintaining stable blood glucose levels would be applicable to different illnesses associated with recurrent hypoglycemia, or wide swings in blood glucose levels. This reviewer anticipates a broader use for raw cornstarch therapy in conditions other than glycogen
SUMMARIES
443
storage disease. Hopefully, along with such reports, information will also become available defining the mechanisms associated with the success of a common kitchen product in maintaining carbohydrate homeostasis in glycogen storage and other diseases. R.J. DECKELBAUM, M.D.
BILE, EICOSANOIDS, PROLIFERATION
AND
COLONIC
CELL
DeRubertis FR, Craven PA, Saito R (Department of Medicine and Pathology, Veterans Administration Medical Center and School of Medicine, University of Pittsburgh, Pittsburgh, Pa.) Bile salt stimulation of colonic epithelial proliferation. Evidence for involvement of lipoxygenase products. J Clin Invest 1984;74:1614-24 (November]. Factors that regulate colonic cell proliferation appear to play an important role in the development of colonic neoplasia. Bile acids, for example, alter colonic mucosal morphology and stimulate epithelial cell proliferation, an action that has been linked to the promotion of experimental colonic cancer (J Lab Clin Med 1979;94:655-60). On the other hand, prostaglandins appear to suppress colonic epithelial proliferation (J Clin Invest 1983;72:1365-75). It is therefore somewhat surprising that bile acids enhance the release of prostaglandin E2 (PGEZ) from the colon. The aim of this study was to assess whether other metabolites of arachidonate could play a role in the stimulation of colonic cell proliferation. Using rat distal colonic segments, it was shown that the in vitro addition of 5 mM deoxycholate (DOC) to rat colon stimulated the release of [r4C]arachidonate within 10 min, and was more potent than an equimolar concentration of either chenodeoxycholate or cholate. Four hours after in vjvo intracolonic instillation of DOC, there was a ninefold increase in colonic ornithine decarboxylase (ODC) activity and 24 h later there was an increase in [“Hlthymidine incorporation into DNA (DNA synthesis). A dose-response relationship between intracolonic DOC and ODC was demonstrated. Chenodeoxycholate and cholate were less potent stimulators of ODC activity. Histologic studies showed no evidence of cell damage or inflammation at 4 h with 10 pmol of DOC, although higher concentrations and longer incubations did show inflammatory changes. Accordingly, this concentration for a 4-h incubation time was used thereafter. In vivo intracolonic instillation of DOC increased the intracolonic accumulation of prostaglandin E (PGE), thromboxane BZ (TXB2), and the lipoxygenase product 12-hydroxyeicosatetraenoic acid (12-HETE) up to four times over the control in 30 min. Intracolonic instillation of indomethacin suppressed both the basal colonic accumulation of PGE and TXBz and the DOC-induced increase. Indomethacin, an inhibitor of cyclooxygenase activity, enhanced 12-HETE accumulation, ODC activity, and DNA synthesis in control and DOC-treated colons. Phenidone (an inhibitor of cyclooxygenase and lipoxygenase) treatment suppressed PGE, TXBp, and 12-HETE accumulation in control and DOC-treated colons but failed to alter basal ODC or DNA synthesis. The DOC-induced
444
SELECTED
GASTROENTEROLOGY
SUMMARIES
increase in ODC and DNA synthesis, however, was abolished by phenidone. A selective inhibitor of thromboxane synthetase, UK 37,248, did not affect ODC activity or DNA synthesis. Indomethacin and phenidone did not inhibit the DOC-mediated increase in [‘4C]arachidonate release. Phenidone pretreatment inhibited the bile acid-induced increases in 12-HETE and ODC activity. Comment.
Bile acids represent one of several intraluminal factors that modulate colonic epithelial proliferative activity. Until this publication it had generally been accepted that bile acids stimulate colonic mitotic activity solely by producing inflammation and superficial lysis of the colonic epithelium. An increase in bile acid production and the subsequent stimulation of colonic cytokinetics has been postulated as an explanation for the promoter action of high dietary fat on colonic cancer (Cancer Res 1981; 41:37OO-5). This report now delineates a second pathway by which bile acids produce a mitogenic response in the colon, namely, the increased accumulation of colonic lipoxygenase products. The stimulation of ODC activity in noninflamed mucosa by bile acids further supports the dissociation of this mitogenic event from colonic cell damage. Bile acids thus increase the generation of both prostanoids (inhibitors of cell proliferation) and lipoxygenase products (enhancers of proliferation). Presumably, a delicate balance must therefore exist within the colonic epithelium between inhibitors and enhancers of cell growth. This balance appears to be helped by the fact that PGE, is generated predominantly in the submucosa, whereas lipoxygenase products may be preferentially formed in the colonic mucosa. A growing body of evidence supports the role of cell proliferation as a critical factor in malignant transformation, in both the colon and other report protissues (Cancer Res 1984;44:4217-23). The present vides new and important information about the factors controlling colonic cell turnover. This type of data may one day enable clinicians to embark on chemoprevention trials designed to regulate colonic cell proliferation, especially in those subjects known to be at high risk for developing large bowel cancer, in whom abnormal patterns of cell proliferation have already been well characterized (Cancer 1974;34:878-88). L.R.JACOBS, M.D.
Reply. The results of our studies with indomethacin indicated that end products of the cyclooxygenase pathway (i.e., prostaglandins and thromboxane) do not mediate bile salt-induced increases in proliferative activity of colonic epithelium. The results with phenidone suggested a role for lipoxygenase products in this action. However, in addition to its effects as an inhibitor of cyclooxygenase and lipoxygenase activities, it should be emphasized that phenidone also is an antioxidant. Thus, our studies with phenidone did not exclude the possibility that bile salt actions on proliferative activity may be mediated by reactive oxygen moieties generated during the oxygenation of arachidonate, rather than by end products of the lipoxygenase pathway. F.K. DKRUBERTIS, M.D.
DETECTING COLON CANCER IN THE CANCER FAMILY SYNDROME Love RR, Morrissey JF (Departments of Human Oncology and Medicine, University of Wisconsin Center for Health Sciences, and the Cancer Prevention Program, Wisconsin Clinical Center, Madison, Wis.) Colonoscopy in asymptomatic individuals with a family history of colorectal cancer. Arch Intern Med 1984;144:2209-11.
Vol.
89, No.
2
The criteria for cancer family syndrome (CFS) have been defined to include (a) an increased frequency of adenocarcinema with a predominance of colon cancer, breast cancer, and endometrial cancer; (b) an early age of onset of the cancers; (c) a high frequency of multiple primary cancers; (d) an autosomal dominant mode of inheritance by segregation ratios; and [e) a high frequency of proximal colon lesions (Gastroenterology 1967;53:517-27). In this report 42 consecutive, asymptomatic members of four kindreds with CFS were screened with colonoscopy. Eight patients had been previously diagnosed as having cancer; of these, 5 patients had had a colorectal malignancy. Patients without a prior cancer diagnosis were all firstdegree relatives of afflicted members of their kindreds. Colonoscopy in these 42 patients revealed seven (17%) “adenomatous/villous polyps.” Two of these seven polyps had invasive cancer, one was a Dukes’ C carcinoma, and the other was a Dukes’ A lesion. Only 2 of the 7 patients with polyps had lesions in the rectosigmoid within reach of a 25-cm sigmoidoscope. Three patients had multiple polyps. Two of the 7 asymptomatic patients found to have neoplasms had had a previous diagnosis of cancer, and 1 patient had asymptomatic ulcerative colitis. The authors concluded that colonoscopy is a useful screening procedure in asymptomatic members of the CFS kindred. Comment. Attempts have been made to control colorectal cancer by improving the early identification of population groups at increased risk for developing this malignancy. It has been assumed that if we can predict groups at increased risk for developing colon cancer we might be able to intervene and prevent these neoplasms, or detect them at an early and curable stage. Screening guidelines for high-risk groups have been suggested but not standardized, and include fecal occult blood tests, sigmoidoscopy and barium enema, and colonoscopy. The most cost-efficient approach to management of high-risk groups has not been clearly defined: however, a multicenter, prospective study is in progress (Am J Gastroenterol 1984;79:824). The authors found a prevalence for adenomas of 17% in their “asymptomatic” patients. The majority of these polyps were beyond the reach of a 25-cm sigmoidoscope. Carcinoma was found in 2 of these patients. However, 1 patient had ulcerative colitis and 2 had had a previous diagnosis of colon cancer, thus placing these 3 patients in a high-risk category for the development of colon cancer, regardless of their family history of cancer. It is unclear in this report which of these 3 patients accounted for the 2 who were found to have cancer. Lynch (Prog Cancer Res Ther Genet Hum Cancer 1977:3:23556) has clearly shown that members of the CFS kindreds have a significant risk of developing colon cancer. We have observed high frequencies of colon cancer in our population registry of familial cancer groups as well, and agree with the need for selective surveillance in this group. Without a control group, however, it is difficult to interpret the significance of the prevalence data for adenomas presented in this paper. Because previous clinical and necropsy studies have reported prevalence rates of adenomas ranging from 7% to 51% in all patients, and as high as 34% for patients under 60 yr of age (Gut 1982;23:835-42, Cancer 1973;31:1260-70, Cancer 1977;39:2258-64, Cancer 1978; 42:2839-48), it would be difficult to support selective screening with colonoscopy based on the 17% adenoma prevalence rate alone. This suggested guideline is based on the predominance of colon cancer in kindreds of the CFS and the autosomal dominant mode of inheritance of adenocarcinomas in this group.
SELECTED
Comment. It is all too infrequent that a simple measure dramatically improves the outcome in debilitating inherited diseases. Now and then, such things do happen. To mention two diseases of interest to gastroenterologists, oral zinc sulfate “cures” patients with acrodermatitis enteropathica, with complete resolution of their severe diarrhea and cutaneous manifestations; vitamin E taken orally prevents the neuromuscular and retinal degeneration of abetalipoproteinemia. The paper by Chen et al. is an important advance in managing patients with type I GSD; it is even better than the continuous nocturnal feeding regime. Severe growth failure, metabolic acidosis, and recurrent hypoglycemia attacks of type I GSD responded poorly to older regimes restricting non-glucose-containing sugars requiring frequent feedings day and night. Following the observations that “bypassing” the liver via portacaval shunting (Ann Surg 1973:178:525-39) or total parenteral nutrition (Surgery 1972;72:306-14) improves most metabolic and clinical anomalies of type I GSD, Green and continuous colleagues (N Engl J Med 1976;294:423-5) introduced nocturnal intragastric clinical and metabolic
feeding. The improvements
marked overall growth and with the nocturnal feeding
regime allowed for wide patient acceptance despite the inconvenience of nightly passage of a nasogastric tube and 12-h connection to a feeding pump. With this regime, patients were further dependent on frequent (every 3 h) daytime snacks or meals. The cornstarch regime does away with the inconveniences and the risks of the tube-feeding regime. Moreover, although not discussed by the authors in the paper under review, patients themselves (and their parents) welcome the cornstarch regime as a major improvement. Our patients in Jerusalem who now follow the cornstarch regime have impressively stable normal blood glucose levels day and night, with little fluctuations after meals or exercise. More important, they feel much better. Continuous normoglycemia with low lactate levels probably helps, but the children are more impressed by being able to eat when they feel like eating, and not by the clock; by eating regular meals with the rest of the family; and by having the choice of varying amounts and types of foods like normal children. (Nonglucose sugars are still restricted, and overall caloric intake and distribution are maintained.) The patients, who were previously well controlled on the continuous nocturnal feeding regime, are themselves surprised by the improvement in mood and well-being since switching to cornstarch therapy. The need to wake up at midnight is a minor inconvenience relative and 6 AM to drink the cornstarch to the other benefits gained by this treatment modality. Similar to the experience of the authors, our youngest patient was unable to sustain normoglycemia for more than 4 h on the cornstarch regime. At 2.5 yr of age, he should have adult levels of pancreatic amylase activity, raising the question that factors other than low amylase activity may be responsible for the poor response to cornstarch in very young patients. Presumably, the success of therapy depends on slow digestion of the uncooked cornstarch, with continuous release and absorption of glucose. Our own first attempts at the cornstarch regime, using locally produced cornflour or cornstarch, were unsuccessful. Only after obtaining the same brand of cornstarch used by the authors were we successful in implementing the regime. This observation, combined with the authors’ observation that hot water or addition of lemonade renders the cornstarch ineffective, suggests that processes used by industry in producing raw cornstarch are important as to whether a particular brand will be effective or not. One might predict that such a simple method for maintaining stable blood glucose levels would be applicable to different illnesses associated with recurrent hypoglycemia, or wide swings in blood glucose levels. This reviewer anticipates a broader use for raw cornstarch therapy in conditions other than glycogen
SUMMARIES
443
storage disease. Hopefully, along with such reports, information will also become available defining the mechanisms associated with the success of a common kitchen product in maintaining carbohydrate homeostasis in glycogen storage and other diseases. R.J. DECKELBAUM, M.D.
BILE, EICOSANOIDS, PROLIFERATION
AND
COLONIC
CELL
DeRubertis FR, Craven PA, Saito R (Department of Medicine and Pathology, Veterans Administration Medical Center and School of Medicine, University of Pittsburgh, Pittsburgh, Pa.) Bile salt stimulation of colonic epithelial proliferation. Evidence for involvement of lipoxygenase products. J Clin Invest 1984;74:1614-24 (November]. Factors that regulate colonic cell proliferation appear to play an important role in the development of colonic neoplasia. Bile acids, for example, alter colonic mucosal morphology and stimulate epithelial cell proliferation, an action that has been linked to the promotion of experimental colonic cancer (J Lab Clin Med 1979;94:655-60). On the other hand, prostaglandins appear to suppress colonic epithelial proliferation (J Clin Invest 1983;72:1365-75). It is therefore somewhat surprising that bile acids enhance the release of prostaglandin E2 (PGEZ) from the colon. The aim of this study was to assess whether other metabolites of arachidonate could play a role in the stimulation of colonic cell proliferation. Using rat distal colonic segments, it was shown that the in vitro addition of 5 mM deoxycholate (DOC) to rat colon stimulated the release of [r4C]arachidonate within 10 min, and was more potent than an equimolar concentration of either chenodeoxycholate or cholate. Four hours after in vjvo intracolonic instillation of DOC, there was a ninefold increase in colonic ornithine decarboxylase (ODC) activity and 24 h later there was an increase in [“Hlthymidine incorporation into DNA (DNA synthesis). A dose-response relationship between intracolonic DOC and ODC was demonstrated. Chenodeoxycholate and cholate were less potent stimulators of ODC activity. Histologic studies showed no evidence of cell damage or inflammation at 4 h with 10 pmol of DOC, although higher concentrations and longer incubations did show inflammatory changes. Accordingly, this concentration for a 4-h incubation time was used thereafter. In vivo intracolonic instillation of DOC increased the intracolonic accumulation of prostaglandin E (PGE), thromboxane BZ (TXB2), and the lipoxygenase product 12-hydroxyeicosatetraenoic acid (12-HETE) up to four times over the control in 30 min. Intracolonic instillation of indomethacin suppressed both the basal colonic accumulation of PGE and TXBz and the DOC-induced increase. Indomethacin, an inhibitor of cyclooxygenase activity, enhanced 12-HETE accumulation, ODC activity, and DNA synthesis in control and DOC-treated colons. Phenidone (an inhibitor of cyclooxygenase and lipoxygenase) treatment suppressed PGE, TXBp, and 12-HETE accumulation in control and DOC-treated colons but failed to alter basal ODC or DNA synthesis. The DOC-induced
444
SELECTED
GASTROENTEROLOGY
SUMMARIES
increase in ODC and DNA synthesis, however, was abolished by phenidone. A selective inhibitor of thromboxane synthetase, UK 37,248, did not affect ODC activity or DNA synthesis. Indomethacin and phenidone did not inhibit the DOC-mediated increase in [‘4C]arachidonate release. Phenidone pretreatment inhibited the bile acid-induced increases in 12-HETE and ODC activity. Comment.
Bile acids represent one of several intraluminal factors that modulate colonic epithelial proliferative activity. Until this publication it had generally been accepted that bile acids stimulate colonic mitotic activity solely by producing inflammation and superficial lysis of the colonic epithelium. An increase in bile acid production and the subsequent stimulation of colonic cytokinetics has been postulated as an explanation for the promoter action of high dietary fat on colonic cancer (Cancer Res 1981; 41:37OO-5). This report now delineates a second pathway by which bile acids produce a mitogenic response in the colon, namely, the increased accumulation of colonic lipoxygenase products. The stimulation of ODC activity in noninflamed mucosa by bile acids further supports the dissociation of this mitogenic event from colonic cell damage. Bile acids thus increase the generation of both prostanoids (inhibitors of cell proliferation) and lipoxygenase products (enhancers of proliferation). Presumably, a delicate balance must therefore exist within the colonic epithelium between inhibitors and enhancers of cell growth. This balance appears to be helped by the fact that PGE, is generated predominantly in the submucosa, whereas lipoxygenase products may be preferentially formed in the colonic mucosa. A growing body of evidence supports the role of cell proliferation as a critical factor in malignant transformation, in both the colon and other report protissues (Cancer Res 1984;44:4217-23). The present vides new and important information about the factors controlling colonic cell turnover. This type of data may one day enable clinicians to embark on chemoprevention trials designed to regulate colonic cell proliferation, especially in those subjects known to be at high risk for developing large bowel cancer, in whom abnormal patterns of cell proliferation have already been well characterized (Cancer 1974;34:878-88). L.R.JACOBS, M.D.
Reply. The results of our studies with indomethacin indicated that end products of the cyclooxygenase pathway (i.e., prostaglandins and thromboxane) do not mediate bile salt-induced increases in proliferative activity of colonic epithelium. The results with phenidone suggested a role for lipoxygenase products in this action. However, in addition to its effects as an inhibitor of cyclooxygenase and lipoxygenase activities, it should be emphasized that phenidone also is an antioxidant. Thus, our studies with phenidone did not exclude the possibility that bile salt actions on proliferative activity may be mediated by reactive oxygen moieties generated during the oxygenation of arachidonate, rather than by end products of the lipoxygenase pathway. F.K. DKRUBERTIS, M.D.
DETECTING COLON CANCER IN THE CANCER FAMILY SYNDROME Love RR, Morrissey JF (Departments of Human Oncology and Medicine, University of Wisconsin Center for Health Sciences, and the Cancer Prevention Program, Wisconsin Clinical Center, Madison, Wis.) Colonoscopy in asymptomatic individuals with a family history of colorectal cancer. Arch Intern Med 1984;144:2209-11.
Vol.
89, No.
2
The criteria for cancer family syndrome (CFS) have been defined to include (a) an increased frequency of adenocarcinema with a predominance of colon cancer, breast cancer, and endometrial cancer; (b) an early age of onset of the cancers; (c) a high frequency of multiple primary cancers; (d) an autosomal dominant mode of inheritance by segregation ratios; and [e) a high frequency of proximal colon lesions (Gastroenterology 1967;53:517-27). In this report 42 consecutive, asymptomatic members of four kindreds with CFS were screened with colonoscopy. Eight patients had been previously diagnosed as having cancer; of these, 5 patients had had a colorectal malignancy. Patients without a prior cancer diagnosis were all firstdegree relatives of afflicted members of their kindreds. Colonoscopy in these 42 patients revealed seven (17%) “adenomatous/villous polyps.” Two of these seven polyps had invasive cancer, one was a Dukes’ C carcinoma, and the other was a Dukes’ A lesion. Only 2 of the 7 patients with polyps had lesions in the rectosigmoid within reach of a 25-cm sigmoidoscope. Three patients had multiple polyps. Two of the 7 asymptomatic patients found to have neoplasms had had a previous diagnosis of cancer, and 1 patient had asymptomatic ulcerative colitis. The authors concluded that colonoscopy is a useful screening procedure in asymptomatic members of the CFS kindred. Comment. Attempts have been made to control colorectal cancer by improving the early identification of population groups at increased risk for developing this malignancy. It has been assumed that if we can predict groups at increased risk for developing colon cancer we might be able to intervene and prevent these neoplasms, or detect them at an early and curable stage. Screening guidelines for high-risk groups have been suggested but not standardized, and include fecal occult blood tests, sigmoidoscopy and barium enema, and colonoscopy. The most cost-efficient approach to management of high-risk groups has not been clearly defined: however, a multicenter, prospective study is in progress (Am J Gastroenterol 1984;79:824). The authors found a prevalence for adenomas of 17% in their “asymptomatic” patients. The majority of these polyps were beyond the reach of a 25-cm sigmoidoscope. Carcinoma was found in 2 of these patients. However, 1 patient had ulcerative colitis and 2 had had a previous diagnosis of colon cancer, thus placing these 3 patients in a high-risk category for the development of colon cancer, regardless of their family history of cancer. It is unclear in this report which of these 3 patients accounted for the 2 who were found to have cancer. Lynch (Prog Cancer Res Ther Genet Hum Cancer 1977:3:23556) has clearly shown that members of the CFS kindreds have a significant risk of developing colon cancer. We have observed high frequencies of colon cancer in our population registry of familial cancer groups as well, and agree with the need for selective surveillance in this group. Without a control group, however, it is difficult to interpret the significance of the prevalence data for adenomas presented in this paper. Because previous clinical and necropsy studies have reported prevalence rates of adenomas ranging from 7% to 51% in all patients, and as high as 34% for patients under 60 yr of age (Gut 1982;23:835-42, Cancer 1973;31:1260-70, Cancer 1977;39:2258-64, Cancer 1978; 42:2839-48), it would be difficult to support selective screening with colonoscopy based on the 17% adenoma prevalence rate alone. This suggested guideline is based on the predominance of colon cancer in kindreds of the CFS and the autosomal dominant mode of inheritance of adenocarcinomas in this group.