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This month in Gastroenterology
THIS MONTH IN
GASTROENTEROLOGY
J. Thomas LaMont
Does Cholecystectomy Increase the Risk of Colon Cancer?
orethan
60 studies have appeared in the medical literature since 1978 addressing the question of whether cholecystectomy increases the risk of colon cancer. From this large number of studies, one might expect a straightforward “yes” or “no” answer, but so far no consensus on this important issue has been reached. In this issue of the journal, two groups of researchers using different techniques have addressed the link between cholecystectomy and subsequent development of colon cancer. Giovannucci et al. at Harvard used the technique of meta-analysis to review 33 case-control studies and 5 cohort studies published over the past 20 years. Metaanalysis allows the pooling of data from many studies provided certain pre-established criteria are met. When the results were pooled, the authors found that the relative risk for colorectal cancer after cholecystectomy increased slightly to 1.24 for females and 1.21 for males. Further analysis of a more limited body of data suggested that cancer risk was higher 10-l 5 years after cholecystectomy and that proximal colonic tumors were more likely to occur than distal ones. The second study, from a single health care region centered in Uppsala, Sweden, involved a population-based cohort study. Ekbom et al. followed up more than 62,000 cholecystectomy patients for up to 23 years and determined that the overall risk for colorectal cancer was not higher after gallbladder removal. However, a slight increase in risk of right-sided colon cancer was observed 15 years or longer after cholecystectomy among women. These two studies suggest that a slight but definite risk for colorectal cancer is observed following cholecystectomy, particularly in the right colon. Although the risk ratio is not large, the number of cholecystectomies performed each year (more than 400,000 in the United States) means
M
that an impressive number of patients may be at risk for colonic cancer 10-l 5 years after surgery. Several possible explanations for these data are discussed, but a common thread appears to be a change in colonic bile salt concentration following cholecystectomy. Certain secondary bile salts may be cocarcinogenic and conceivably could hasten the multistep progression of coionic adenomas to carcinomas. These studies also point out that right- and left-sided colon cancers may arise from different pathophysiological mechanisms. . . . pages 130, 142
The T lymphocyte in Alcoholic Liver Disease: Bystander or Culprit? hy a minority of alcoholics develop progressive alcoholic liver disease (ALD) remains something of a mystery. Fatty liver appears to be a dose-dependent effect of heavy alcohol intake, but only lo%-20% of chronic alcoholics develop alcoholic hepatitis or cirrhosis. Immunologic injury has been postulated as a possible mechanism to explain differences in host response to ALD. In this issue, Chedid et al. report on a multicenter VA study of the possible role of cell-mediated hepatic injury in ALD. Liver biopsy specimens from 144 patients with severe ALD were examined by immunohistochemical techniques for T- and B-lymphocyte markers that allow identification of lymphocytes in liver tissue as T-helper cells, T-cytotoxic cells, B-lymphocytes, and natural killer (NK) cells. Their results indicate that T lymphocytes were rarely observed in normal liver specimens, but with progression of ALD, CD4+ and CD8+ T cells were greater in both alcoholic hepatitis and cirrhosis. These invading lymphocytes surrounded regenerating nodules in areas of piecemeal necrosis and were also found within fibrotic bands. B lymphocytes were observed in only 7% of ALD biopsy specimens. In addition, both class I and class III major histo-
W
compatibility complex molecules were expressed on the surface of hepatocytes in ALD. These results are compatible with the hypothesis that immune damage mediated by T lymphocytes may be an important factor in the pathogenesis of ALD. It is not yet clear whether cellmediated immune injury is the cause or the consequence of ALD, but it seems unlikely that these infiltrating lymphocytes are simply innocent bystanders. In a host of other diseases, T lymphocytes in sites of inflammation are thought to be a major source of tissue damage. More importantly, these results suggest that targeted immunotherapy may be of potential benefit in treating patients with severe ALD. . . . page 254
Platelet and Neutrophil Impairment in Cirrhosis latelet and neutrophil
abnormali-
P ties are well described in cirrhotic patients. Evidence has accumulated recently to indicate that functional defects of these cells cannot simply be explained by thrombocytopenia or leukopenia or by the toxic effects of ethanol. Two papers by Laffi et al. of Florence, Italy, describe detailed studies of platelet and neutrophil function in cirrhotics. Their results indicate that signal transduction is severely impaired in platelets and neutrophils and that separate pathways are involved in both cell types. First the platelets. In end-stage cirrhosis, platelet aggregation is often defective, and the defect is related to the degree of liver impairment. Activation and aggregation of platelets involves a series of biochemical events starting with binding of agonists such as thrombin to cell surface receptors, activation of phospholipase C, and release of the second messengers inositol triphosphate (IPs) and diacylglycerol. IP, triggers a secondary release of Ca’+ within the platelet, and diacylglycerol activates protein kinase C. These com(ctmtinnedon mxt page) QASlROEMEROLO9Y 1993;105:1-2
THIS MONTH IN
GASTROENTEROLOGY (continued)
pounds in turn activate a molecular cascade within the platelet that eventually results in their aggregation to form a blood clot. Curiously, cyclic adenosine monophosphate and cyclic guanosine monophosphate, which are typically involved in activation pathways in most other cells, cause inhibition of platelet activation. To study this rather complex series of events Laffi et al. isolated platelets from cirrhotics and normal patients and stimulated them in vitro with known platelet activators. The level of activation of platelets in cirrhotics, as measured by IP, generation and Ca*+ concentration, was considerably diminished compared with normals. An interesting finding was that baseline cyclic nucleotide levels were greater in platelets of cirrhotics, suggesting that a metabolic brake is operative in these cells before activation. Reduced neutrophil function may play a central role in the impaired response to infection observed in cirCirrhotic neutrophils are rhotics. known to be defective with regard to phagocytosis, chemotaxis, generation of superoxide anion, degranulation, and intracellular killing of bacteria. In this study, Laffi et al. compared the in vitro response of neutrophils from nonalcoholic cirrhotics and normals with stimulation by known activators. Compared with normals, neutrophils in cirrhotics were not as responsive, as shown by a diminished release of superoxide anion, leukotriene B,, and platelet-activating factor. The authors speculate that one mechanism to explain their findings is that endotoxemia, a common finding in cirrhotics, may chronically activate neutrophils, making them refractory to other stimuli. These two papers provide solid evidence that cirrhosis has a profound effect on normal cellular responses in platelets and neutrophils. The next step will be to determine why these defects occur and whether they are amenable to therapy.
. . . pages 148, 170
2
Predicting the Future for Patients with Cirrhosis
I
n the April issue, a paper from Barcelona reported on the use of multivariate analysis to predict the risk factors for spontaneous bacterial peritonitis in cirrhotics. In this issue, another group from Barcelona uses the same type of statistical analysis to predict the occurrence of hepatorenal syndrome (HRS) in cirrhosis. Gines et al. followed up 234 nonazotemic cirrhotic patients of various etiologies for a loyear period between 1980 and 1990. They analyzed 39 clinical and laboratory values to determine which might predict the development of HRS. HRS occurred in 18% of their study group at 1 year and 39% at 5 years. As expected, HRS was more common after a complication such as infection or bleeding. Once HRS was established, the median survival time was less than 2 weeks, a prognosis similar to that in fulminant hepatic failure. A number of factors were associated with a high risk for HRS: absence of hepatomegaly, poor nutrition, and presence of varices. In addition, factors related to altered systemic circulation and impaired renal function including hyponatremia and high plasma renin activity were associated with HRS. Surprisingly, traditional liver function tests, underlying cause of cirrhosis, and Childs score did not predict HRS. This study identifies a number of variables that should facilitate our ability to identify patients who are at high risk for HRS. The authors make a plea that cirrhotics should undergo liver transplantation before they develop HRS, because the results of liver transplantation are much worse after this complication occurs.
. . . page 229
Crohn’s Monocytea Are PrZmedfor Action
W
hat triggers intestinal inflammation in Crohn’s disease (CD)? A leading candidate is the macrophage/
monocyte, a phagocytic cell of the lamina propria that is thought to coordinate the activation of the intestinal inflammatory response by releasing inflammatory mediators. One theory holds that increased mucosal permeability in the intestine of patients with inflammatory bowel disease allows bacterial products including lipopolysaccharide (LPS) and chemotactic peptides to enter tissues and up-regulate inflammatory cells. These cells would thus be primed and ready to release mediators with miminal stimulation. Baldassano et al. from Philadelphia studied the peripheral blood monocyte population of teenagers with CD to evaluate the secretion of superoxide radicals in response to a standard stimulus. Their results indicate that monocytes from patients with active CD release more superoxide compared with patients with quiescent CD or healthy controls. This hyperactivity was not specific for CD, because monocytes from patients with other inflammatory conditions including ulcerative colitis and rheumatoid arthritis also released more superoxide when stimulated. To determine the cause of the increased monocyte response, Baldassano et al. examined the possible involvement of bacterial LPS in their results. LPS, a product of intestinal gram-negative bacteria, does not itself trigger release of superoxide, but it is capable of priming monocytes to respond more strongly to other stimuli. To examine the role of LPS the investigators showed that CD serum primed normal monocytes to release more superoxide upon stimulation and that the priming effect was greatly reduced when LPS was removed from CD sera. The authors speculate that during active CD the intestinal mucosa is leaky, allowing uptake of LPS, which primes monocytes. These primed monocytes are then much more likely to release inflammatory mediators when they are stimulated.
. . . page 60
GASTROENTEROLOGY
J. Thomas LaMont
Does Cholecystectomy Increase the Risk of Colon Cancer?
orethan
60 studies have appeared in the medical literature since 1978 addressing the question of whether cholecystectomy increases the risk of colon cancer. From this large number of studies, one might expect a straightforward “yes” or “no” answer, but so far no consensus on this important issue has been reached. In this issue of the journal, two groups of researchers using different techniques have addressed the link between cholecystectomy and subsequent development of colon cancer. Giovannucci et al. at Harvard used the technique of meta-analysis to review 33 case-control studies and 5 cohort studies published over the past 20 years. Metaanalysis allows the pooling of data from many studies provided certain pre-established criteria are met. When the results were pooled, the authors found that the relative risk for colorectal cancer after cholecystectomy increased slightly to 1.24 for females and 1.21 for males. Further analysis of a more limited body of data suggested that cancer risk was higher 10-l 5 years after cholecystectomy and that proximal colonic tumors were more likely to occur than distal ones. The second study, from a single health care region centered in Uppsala, Sweden, involved a population-based cohort study. Ekbom et al. followed up more than 62,000 cholecystectomy patients for up to 23 years and determined that the overall risk for colorectal cancer was not higher after gallbladder removal. However, a slight increase in risk of right-sided colon cancer was observed 15 years or longer after cholecystectomy among women. These two studies suggest that a slight but definite risk for colorectal cancer is observed following cholecystectomy, particularly in the right colon. Although the risk ratio is not large, the number of cholecystectomies performed each year (more than 400,000 in the United States) means
M
that an impressive number of patients may be at risk for colonic cancer 10-l 5 years after surgery. Several possible explanations for these data are discussed, but a common thread appears to be a change in colonic bile salt concentration following cholecystectomy. Certain secondary bile salts may be cocarcinogenic and conceivably could hasten the multistep progression of coionic adenomas to carcinomas. These studies also point out that right- and left-sided colon cancers may arise from different pathophysiological mechanisms. . . . pages 130, 142
The T lymphocyte in Alcoholic Liver Disease: Bystander or Culprit? hy a minority of alcoholics develop progressive alcoholic liver disease (ALD) remains something of a mystery. Fatty liver appears to be a dose-dependent effect of heavy alcohol intake, but only lo%-20% of chronic alcoholics develop alcoholic hepatitis or cirrhosis. Immunologic injury has been postulated as a possible mechanism to explain differences in host response to ALD. In this issue, Chedid et al. report on a multicenter VA study of the possible role of cell-mediated hepatic injury in ALD. Liver biopsy specimens from 144 patients with severe ALD were examined by immunohistochemical techniques for T- and B-lymphocyte markers that allow identification of lymphocytes in liver tissue as T-helper cells, T-cytotoxic cells, B-lymphocytes, and natural killer (NK) cells. Their results indicate that T lymphocytes were rarely observed in normal liver specimens, but with progression of ALD, CD4+ and CD8+ T cells were greater in both alcoholic hepatitis and cirrhosis. These invading lymphocytes surrounded regenerating nodules in areas of piecemeal necrosis and were also found within fibrotic bands. B lymphocytes were observed in only 7% of ALD biopsy specimens. In addition, both class I and class III major histo-
W
compatibility complex molecules were expressed on the surface of hepatocytes in ALD. These results are compatible with the hypothesis that immune damage mediated by T lymphocytes may be an important factor in the pathogenesis of ALD. It is not yet clear whether cellmediated immune injury is the cause or the consequence of ALD, but it seems unlikely that these infiltrating lymphocytes are simply innocent bystanders. In a host of other diseases, T lymphocytes in sites of inflammation are thought to be a major source of tissue damage. More importantly, these results suggest that targeted immunotherapy may be of potential benefit in treating patients with severe ALD. . . . page 254
Platelet and Neutrophil Impairment in Cirrhosis latelet and neutrophil
abnormali-
P ties are well described in cirrhotic patients. Evidence has accumulated recently to indicate that functional defects of these cells cannot simply be explained by thrombocytopenia or leukopenia or by the toxic effects of ethanol. Two papers by Laffi et al. of Florence, Italy, describe detailed studies of platelet and neutrophil function in cirrhotics. Their results indicate that signal transduction is severely impaired in platelets and neutrophils and that separate pathways are involved in both cell types. First the platelets. In end-stage cirrhosis, platelet aggregation is often defective, and the defect is related to the degree of liver impairment. Activation and aggregation of platelets involves a series of biochemical events starting with binding of agonists such as thrombin to cell surface receptors, activation of phospholipase C, and release of the second messengers inositol triphosphate (IPs) and diacylglycerol. IP, triggers a secondary release of Ca’+ within the platelet, and diacylglycerol activates protein kinase C. These com(ctmtinnedon mxt page) QASlROEMEROLO9Y 1993;105:1-2
THIS MONTH IN
GASTROENTEROLOGY (continued)
pounds in turn activate a molecular cascade within the platelet that eventually results in their aggregation to form a blood clot. Curiously, cyclic adenosine monophosphate and cyclic guanosine monophosphate, which are typically involved in activation pathways in most other cells, cause inhibition of platelet activation. To study this rather complex series of events Laffi et al. isolated platelets from cirrhotics and normal patients and stimulated them in vitro with known platelet activators. The level of activation of platelets in cirrhotics, as measured by IP, generation and Ca*+ concentration, was considerably diminished compared with normals. An interesting finding was that baseline cyclic nucleotide levels were greater in platelets of cirrhotics, suggesting that a metabolic brake is operative in these cells before activation. Reduced neutrophil function may play a central role in the impaired response to infection observed in cirCirrhotic neutrophils are rhotics. known to be defective with regard to phagocytosis, chemotaxis, generation of superoxide anion, degranulation, and intracellular killing of bacteria. In this study, Laffi et al. compared the in vitro response of neutrophils from nonalcoholic cirrhotics and normals with stimulation by known activators. Compared with normals, neutrophils in cirrhotics were not as responsive, as shown by a diminished release of superoxide anion, leukotriene B,, and platelet-activating factor. The authors speculate that one mechanism to explain their findings is that endotoxemia, a common finding in cirrhotics, may chronically activate neutrophils, making them refractory to other stimuli. These two papers provide solid evidence that cirrhosis has a profound effect on normal cellular responses in platelets and neutrophils. The next step will be to determine why these defects occur and whether they are amenable to therapy.
. . . pages 148, 170
2
Predicting the Future for Patients with Cirrhosis
I
n the April issue, a paper from Barcelona reported on the use of multivariate analysis to predict the risk factors for spontaneous bacterial peritonitis in cirrhotics. In this issue, another group from Barcelona uses the same type of statistical analysis to predict the occurrence of hepatorenal syndrome (HRS) in cirrhosis. Gines et al. followed up 234 nonazotemic cirrhotic patients of various etiologies for a loyear period between 1980 and 1990. They analyzed 39 clinical and laboratory values to determine which might predict the development of HRS. HRS occurred in 18% of their study group at 1 year and 39% at 5 years. As expected, HRS was more common after a complication such as infection or bleeding. Once HRS was established, the median survival time was less than 2 weeks, a prognosis similar to that in fulminant hepatic failure. A number of factors were associated with a high risk for HRS: absence of hepatomegaly, poor nutrition, and presence of varices. In addition, factors related to altered systemic circulation and impaired renal function including hyponatremia and high plasma renin activity were associated with HRS. Surprisingly, traditional liver function tests, underlying cause of cirrhosis, and Childs score did not predict HRS. This study identifies a number of variables that should facilitate our ability to identify patients who are at high risk for HRS. The authors make a plea that cirrhotics should undergo liver transplantation before they develop HRS, because the results of liver transplantation are much worse after this complication occurs.
. . . page 229
Crohn’s Monocytea Are PrZmedfor Action
W
hat triggers intestinal inflammation in Crohn’s disease (CD)? A leading candidate is the macrophage/
monocyte, a phagocytic cell of the lamina propria that is thought to coordinate the activation of the intestinal inflammatory response by releasing inflammatory mediators. One theory holds that increased mucosal permeability in the intestine of patients with inflammatory bowel disease allows bacterial products including lipopolysaccharide (LPS) and chemotactic peptides to enter tissues and up-regulate inflammatory cells. These cells would thus be primed and ready to release mediators with miminal stimulation. Baldassano et al. from Philadelphia studied the peripheral blood monocyte population of teenagers with CD to evaluate the secretion of superoxide radicals in response to a standard stimulus. Their results indicate that monocytes from patients with active CD release more superoxide compared with patients with quiescent CD or healthy controls. This hyperactivity was not specific for CD, because monocytes from patients with other inflammatory conditions including ulcerative colitis and rheumatoid arthritis also released more superoxide when stimulated. To determine the cause of the increased monocyte response, Baldassano et al. examined the possible involvement of bacterial LPS in their results. LPS, a product of intestinal gram-negative bacteria, does not itself trigger release of superoxide, but it is capable of priming monocytes to respond more strongly to other stimuli. To examine the role of LPS the investigators showed that CD serum primed normal monocytes to release more superoxide upon stimulation and that the priming effect was greatly reduced when LPS was removed from CD sera. The authors speculate that during active CD the intestinal mucosa is leaky, allowing uptake of LPS, which primes monocytes. These primed monocytes are then much more likely to release inflammatory mediators when they are stimulated.
. . . page 60