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Asymptomatic PSC—Do they really have progressive diseases?
294
CORRESPONDENCE
GASTROENTEROLOGY Vol. 100. No. 1
in affecting the metabolism of connective of the alcoholics.
tissues and the prognosis
ONNI MEMELA, M.D., PH.D. JUHA RISTELI. M.D., PH.D. LEILA RISTELI, M.D., PH.D.
Collagen Research Unit Departments of Clinical Chemistry and Medical Biochemistry University of Oulu Oulu, Finland JOAN E. BLAKE, M. Ser. KATHLEEN V. COMPTON, R.N. HECTORORREGO,M.D.,F.R.C.P.(C)
Addiction Research Foundation Toronto, Ontario, Canada
Asymptomatic PSC-Do Progressive Diseases?
They Really Have
Dear Sir: The report on primary sclerosing cholangitis (PSC) by Porayko et al. (l), although an interesting one, appears to suffer from a subtle flaw in design. The entry criteria established by the authors are ambiguous. Fatigue, which in addition to pruritus is an important symptom of PSC, was not included. Many patients (number not reported) with right upper quadrant abdominal pain “believed to be nonbiliary in origin” were included, and this certainly introduces an element of selection bias. Thirty-eight percent of the patients in the study group were referred to the Mayo Clinic because of abnormal cholangiography. The authors do not indicate why cholangiography was performed on these patients in the absence of symptoms or abnormal liver test results. Also, inclusion of patients who had undergone cholecystectomy based on abnormal results of liver tests in the absence of symptoms makes the data equivocal in this retrospective prospective study. This group accounted for 20% of the patient population in this study. However, it is not a routine clinical practice to perform cholecystectomy solely on the basis of abnormal liver test results in the absence of symptoms and other objective test results supporting cholecystitis. Therefore, it appears that in fact symptoms or signs of cholestatic liver disease were overlooked in the recording of data in patient charts at the time of cholecystectomy. One of the criteria for progression of PSC in this study was jaundice. The authors report that 12 of 45 patients with PSC developed jaundice, although 9 patients had bilirubin concentrations > 1.1 mg/dL on entry but jaundice was not “clinically detectable.” It is possible that icterus might have been missed or not recorded in these patients. Portal hypertension as evidenced by the formation of esophageal or peristomal varices developed in 13 patients, although 10 patients were not evaluated for the presence of varices at the time of study entry. The authors note that individual physical signs at the time of study entry, including esophageal varices and ascites, were not found to be useful predictors of disease outcome. This assumption may be incorrect regarding esophageal varices and ascites, as ascites was not present in any patient at the time of study entry and the status of esophageal varices in 10 patients was unknown at entry. We hope to seek further clarifications from the authors on these points. ATIJL VAHIL, M.D. KAKESH GUPTA, M.D.
Our Lady of Mercy Medical Center Bronx, New York 1. Porayko MK, Wiesner
RI-I, LaRusso NF, Ludwig J, MacCarthy RL, Steiner BL, Twomey CK, Zinsmeister AR. Patients with
asymptomatic primary sclerosing cholangitis frequently progressive disease. Gastroenterology 1990;98:1594-1602.
have
Reply. Drs. Vahil and Gupta state that the entry criteria established for this study are ambiguous. Keeping in mind that this is a retrospective study and that fatigue can be a result of concurrent inflammatory bowel disease as well as liver disease, we felt that fatigue was not as important a symptom in primary sclerosing cholangitis as it is in a disease such as primary biliary cirrhosis. However, in reviewing the data from these 45 patients, it is noted that only 6 of these patients had mild fatigue at study entry; furthermore, 13 patients had no mention of whether they had fatigue or not, and in 26 patients fatigue was not a complaint. There was no difference regarding progression of the disease in those patients in whom fatigue was not noted or was not present compared with those patients in whom fatigue was present. The comment is also made that many patients with right upper quadrant abdominal pain believed to be nonbiliary in origin were included in this study, and that this may possibly introduce a bias. In reality, as is stated in the paper, only a single patient had a complaint of vague right quadrant abdominal pain. This patient underwent a cholecystectomy and remained free of symptoms for 5 years before the diagnosis of primary sclerosing cholangitis was made. In this case, we felt the right upper quadrant pain was associated with gallbladder disease, and because primary sclerosing cholangitis was not diagnosed at the time of surgery but was eventually diagnosed only after 5 years of further follow-up, we felt the pain was secondary to gallbladder disease and not related to primary sclerosing cholangitis. All patients with liver enzyme abnormalities and abdominal pain, as stated in the entry criteria, were excluded from this study. The comment is made that 38% of patients in the study were referred to the Mayo Clinic because of abnormal cholangiography, and the question is posed why cholangiography was performed on these patients in the absence of symptoms or abnormal results of liver function tests. In reality, these patients all had the diagnosis of primary sclerosing cholangitis made at home on the basis of cholangiography, and in all instances, these studies were performed because of abnormal liver function test results, in particular an elevated serum level of alkaline phosphatase. When the patients were seen at the Mayo Clinic, cholangiography was repeated to confirm the diagnosis and to exclude stone disease or a concurrent bile duct cancer at the time of study entry. Thus, in almost all instances, cholangiography was performed at home because of abnormal results of liver function tests in the absence of symptoms related to primary sclerosing cholangitis. A further comment was made regarding performing cholecystectomy based on abnormal liver function test results in the absence of symptoms. In each instance, the operative and preoperative notes were carefully reviewed. In 8 of the 9 patients, a cholecystectomy was performed because of an elevated serum level of alkaline phosphatase and a nonvisualized oral cholecystogram study. In carefully reviewing the charts and in questioning the patients, these patients were found to not have symptoms related to gallbladder or biliary disease. Thus, we believe that symptoms and signs of cholestatic liver disease were not overloaded in recording the data from the charts of these patients at the time of cholecystectomy, as is implicated in the above comments. A comment is made regarding jaundice, and the letter notes that 9 patients had a bilirubin level > 1.1 mg/dL and suggest that icteris might have been missed on physical examination. As is noted in Table 1 in our paper, the range of serum bilirubin levels in this group of patients at study entry was 0.3-2.7 mg/dL. I believe it is well established that it is difficult or impossible to detect jaundice
CORRESPONDENCE
January 1991
when serum bilirubin levels are < 3 mg/dL. Thus, I believe the data are quite consistent that icteris was not detected in these patients at study entry. Finally, a comment is made that 10 of the study patients did not undergo an upper endoscopy or barium swallow to evaluate for the presence of varices, and that our assumption that varices and ascites are not useful predictors of disease outcome may be incorrect. Indeed, we strongly believe that the presence of esophageal varices and ascites is indeed a predictor of outcome, as we have noted in previous publications on the natural history of primary sclerosing cholangitis (1). Furthermore, in our entry criteria, we clearly note that the presence of ascites or edema or variceal bleeding were specific symptoms that would lead to exclusion of these patients from this asymptomatic study. We hope that these comments do clarify the concerns that were raised. RUSSELL H. WIESNER, M.D.
Mayo Clinic Rochester, Minnesota 1. Wiesner
RH, Grambsch PM, Dickson ER, Ludwig J, MacCarty RL, Hunter EB, Fleming TR, Fisher LD, Beaver SJ, LaRusso NF. Primary sclerosing cholangitis: natural history, prognostic factors and survival analysis. Hepatology 1989;10(4):430-436.
Chronic
Alcohol
Ingestion
and Nutrition
Dear Sir: Korsten et al. state “the mean energy intake per rat in each group using our system of feeding was 230 kcal/kg per day, which is comparable to that consumed by animals pair-fed liquid diets of standard composition” (1). However, with the same liquid diet model, Lieber et al. claims a considerably greater amount of energy intake (400 kcal/kg per day) (2). The reason for this discrepancy is unknown. Korsten et al. report that young growing rats in group III of their study consumed a nutritionally adequate diet with ethanol for 28 days, and their body weight change was -1.7% ? 7.5% (1). How can the diet be nutritionally adequate if when fed, young rats did not grow? Even when rats were fed the nutritionally adequate diet without alcohol (group IV), they gained only 29.5% ? 5.1%, which is meager compared with the growth of rats fed the various known nutritionally adequate diets. For example, a 120-g rat must weigh about 316 g after being fed the nutritionally adequate AINor NIH-07 diets for 28 days (3), causing an increase of about 163% in body weight. It is unfortunate that the nutritional inadequacy of the liquid ethanol diet model is not yet appreciated despite numerous investigations addressing this aspect in recent years (4). An understanding of the role of nutrition can only advance research and improve our knowledge of the effects of chronic alcohol consumption. G. ANANDARAO, PHD. EDWARD C. LARKIN, M.D.
Alcohol Research Laboratory [151H) VeteransAdministration Medical Center 150 Muir Road Martinez, California 94553
1. Korsten MA, Wilson JS, Lieber CS. Interactive effects of dietary protein and ethanol on rat pancreas. Gastroenterology 1990;99: 229-236. 2. Lieber CS, DeCarli LM, Sorrel1 MF. Experimental methods of ethanol administration. Hepatology 1989;10:501-510.
295
3. Bieri JG, Stoewsand GS, Briggs GM, Phillips RW, Woodard JC, Knapka JJ. Report of the American Institute of Nutrition Ad Hoc Committee on standards for nutritional studies. J Nutr 1977;107: 1340-1348. 4. Rao GA, Larkin EC, Derr RF. Effects of chronic alcohol ingestion: role of nutritional factors. Biochem Arch 1989:5:289-296. Reply. The energy intake of rats using the Lieber-DeCarli liquid diet technique will necessarily vary according to study design and purpose. In our recent publication (l), we investigated the combined effects of protein deficiency and ethanol intake on pancreatic function. Inasmuch as protein-deficient rats fed ethanol were generally poor eaters, the mean energy consumption of rats in groups II, III, and N (protein deficient without ethanol, protein sufficient with ethanol, and protein sufficient without ethanol, respectively) was in the low range of normal and was not as high as that observed in less restrictive settings (2). However, by matching the overall caloric intake of groups II-IV with that consumed by the rats fed ethanol with protein-deficient diets (group I), we were able to study the role of protein deficiency without the confounding effects of differences in energy intake. Growth retardation was apparent in our rats despite feeding of protein-sufficient diets, probably as a consequence of restriction in nutrient intake. Despite slower rates of growth, however, animals receiving protein-sufficient diets (group IV) appeared healthy and did not show pathological changes at death. The healthy appearance of these rats supports the concept that moderate undernutrition without malnutrition is not detrimental. There is, in fact, experimental evidence that such a stage may actually be more favorable than ad libitum nutrition. This has been noted in relationship to bone composition (3) longevity (4) and susceptibility to disease (5), including spontaneously occurring neoplasms (6) and tumors secondary to radiation (7). Finally, notwithstanding our long-term interest in the direct toxicity of ethanol, we also are exploring the effects of nutrition on alcohol-induced pathology; hence the present study. The liquid diet technique permitted us to study the role of one nutritional factor, namely dietary protein, in a controlled and reproducible manner. MARKA. KORSTEN,M.D. JEREMYS. WILSON,M.D. CHARLES S. LIEBER, M.D.
Veterans Administration Medical Center I 151 G 130 West Kingsbridge Road Bronx, New York 10468-3994
1. Korsten MA, Wilson JS, Lieber CS. Interactive effects of dietary protein and ethanol on rat pancreas. Gastroenterology 1990;99: 229-236. 2. Lieber CS, DeCarli LM, Sorrel1 MF. Experimental methods of ethanol administration. Hepatology 1989;10:501-510. 3. Saville PD, Lieber CS. Increases in skeletal calcium and femur cortex thickness produced by undernutrition. Nutr 1969;99:141144. 4. 5.
6. 7.
Barrows CH. Nutrition, aging, and genetic program. Am J Clin Nutr 1972;25:829-833. Yu BP, Masoro EJ, Murata I, Bertrand HA and Lynd FT. Life span of SPF Fischer 344 male rats fed ad libitum or restricted diets. J Gerontol 1982;37:130-141. Weindruch R, Walford RL. Dietary restriction in mice beginning a 1 year of age. Science 1982;215:1415-1418. Gross L, Dreyfuss Y. Reduction in the incidence of radiationinduced tumors in rats after restriction of food intake. Proc Nat1 Acad Sci USA 1984;81:7596-7598.
CORRESPONDENCE
GASTROENTEROLOGY Vol. 100. No. 1
in affecting the metabolism of connective of the alcoholics.
tissues and the prognosis
ONNI MEMELA, M.D., PH.D. JUHA RISTELI. M.D., PH.D. LEILA RISTELI, M.D., PH.D.
Collagen Research Unit Departments of Clinical Chemistry and Medical Biochemistry University of Oulu Oulu, Finland JOAN E. BLAKE, M. Ser. KATHLEEN V. COMPTON, R.N. HECTORORREGO,M.D.,F.R.C.P.(C)
Addiction Research Foundation Toronto, Ontario, Canada
Asymptomatic PSC-Do Progressive Diseases?
They Really Have
Dear Sir: The report on primary sclerosing cholangitis (PSC) by Porayko et al. (l), although an interesting one, appears to suffer from a subtle flaw in design. The entry criteria established by the authors are ambiguous. Fatigue, which in addition to pruritus is an important symptom of PSC, was not included. Many patients (number not reported) with right upper quadrant abdominal pain “believed to be nonbiliary in origin” were included, and this certainly introduces an element of selection bias. Thirty-eight percent of the patients in the study group were referred to the Mayo Clinic because of abnormal cholangiography. The authors do not indicate why cholangiography was performed on these patients in the absence of symptoms or abnormal liver test results. Also, inclusion of patients who had undergone cholecystectomy based on abnormal results of liver tests in the absence of symptoms makes the data equivocal in this retrospective prospective study. This group accounted for 20% of the patient population in this study. However, it is not a routine clinical practice to perform cholecystectomy solely on the basis of abnormal liver test results in the absence of symptoms and other objective test results supporting cholecystitis. Therefore, it appears that in fact symptoms or signs of cholestatic liver disease were overlooked in the recording of data in patient charts at the time of cholecystectomy. One of the criteria for progression of PSC in this study was jaundice. The authors report that 12 of 45 patients with PSC developed jaundice, although 9 patients had bilirubin concentrations > 1.1 mg/dL on entry but jaundice was not “clinically detectable.” It is possible that icterus might have been missed or not recorded in these patients. Portal hypertension as evidenced by the formation of esophageal or peristomal varices developed in 13 patients, although 10 patients were not evaluated for the presence of varices at the time of study entry. The authors note that individual physical signs at the time of study entry, including esophageal varices and ascites, were not found to be useful predictors of disease outcome. This assumption may be incorrect regarding esophageal varices and ascites, as ascites was not present in any patient at the time of study entry and the status of esophageal varices in 10 patients was unknown at entry. We hope to seek further clarifications from the authors on these points. ATIJL VAHIL, M.D. KAKESH GUPTA, M.D.
Our Lady of Mercy Medical Center Bronx, New York 1. Porayko MK, Wiesner
RI-I, LaRusso NF, Ludwig J, MacCarthy RL, Steiner BL, Twomey CK, Zinsmeister AR. Patients with
asymptomatic primary sclerosing cholangitis frequently progressive disease. Gastroenterology 1990;98:1594-1602.
have
Reply. Drs. Vahil and Gupta state that the entry criteria established for this study are ambiguous. Keeping in mind that this is a retrospective study and that fatigue can be a result of concurrent inflammatory bowel disease as well as liver disease, we felt that fatigue was not as important a symptom in primary sclerosing cholangitis as it is in a disease such as primary biliary cirrhosis. However, in reviewing the data from these 45 patients, it is noted that only 6 of these patients had mild fatigue at study entry; furthermore, 13 patients had no mention of whether they had fatigue or not, and in 26 patients fatigue was not a complaint. There was no difference regarding progression of the disease in those patients in whom fatigue was not noted or was not present compared with those patients in whom fatigue was present. The comment is also made that many patients with right upper quadrant abdominal pain believed to be nonbiliary in origin were included in this study, and that this may possibly introduce a bias. In reality, as is stated in the paper, only a single patient had a complaint of vague right quadrant abdominal pain. This patient underwent a cholecystectomy and remained free of symptoms for 5 years before the diagnosis of primary sclerosing cholangitis was made. In this case, we felt the right upper quadrant pain was associated with gallbladder disease, and because primary sclerosing cholangitis was not diagnosed at the time of surgery but was eventually diagnosed only after 5 years of further follow-up, we felt the pain was secondary to gallbladder disease and not related to primary sclerosing cholangitis. All patients with liver enzyme abnormalities and abdominal pain, as stated in the entry criteria, were excluded from this study. The comment is made that 38% of patients in the study were referred to the Mayo Clinic because of abnormal cholangiography, and the question is posed why cholangiography was performed on these patients in the absence of symptoms or abnormal results of liver function tests. In reality, these patients all had the diagnosis of primary sclerosing cholangitis made at home on the basis of cholangiography, and in all instances, these studies were performed because of abnormal liver function test results, in particular an elevated serum level of alkaline phosphatase. When the patients were seen at the Mayo Clinic, cholangiography was repeated to confirm the diagnosis and to exclude stone disease or a concurrent bile duct cancer at the time of study entry. Thus, in almost all instances, cholangiography was performed at home because of abnormal results of liver function tests in the absence of symptoms related to primary sclerosing cholangitis. A further comment was made regarding performing cholecystectomy based on abnormal liver function test results in the absence of symptoms. In each instance, the operative and preoperative notes were carefully reviewed. In 8 of the 9 patients, a cholecystectomy was performed because of an elevated serum level of alkaline phosphatase and a nonvisualized oral cholecystogram study. In carefully reviewing the charts and in questioning the patients, these patients were found to not have symptoms related to gallbladder or biliary disease. Thus, we believe that symptoms and signs of cholestatic liver disease were not overloaded in recording the data from the charts of these patients at the time of cholecystectomy, as is implicated in the above comments. A comment is made regarding jaundice, and the letter notes that 9 patients had a bilirubin level > 1.1 mg/dL and suggest that icteris might have been missed on physical examination. As is noted in Table 1 in our paper, the range of serum bilirubin levels in this group of patients at study entry was 0.3-2.7 mg/dL. I believe it is well established that it is difficult or impossible to detect jaundice
CORRESPONDENCE
January 1991
when serum bilirubin levels are < 3 mg/dL. Thus, I believe the data are quite consistent that icteris was not detected in these patients at study entry. Finally, a comment is made that 10 of the study patients did not undergo an upper endoscopy or barium swallow to evaluate for the presence of varices, and that our assumption that varices and ascites are not useful predictors of disease outcome may be incorrect. Indeed, we strongly believe that the presence of esophageal varices and ascites is indeed a predictor of outcome, as we have noted in previous publications on the natural history of primary sclerosing cholangitis (1). Furthermore, in our entry criteria, we clearly note that the presence of ascites or edema or variceal bleeding were specific symptoms that would lead to exclusion of these patients from this asymptomatic study. We hope that these comments do clarify the concerns that were raised. RUSSELL H. WIESNER, M.D.
Mayo Clinic Rochester, Minnesota 1. Wiesner
RH, Grambsch PM, Dickson ER, Ludwig J, MacCarty RL, Hunter EB, Fleming TR, Fisher LD, Beaver SJ, LaRusso NF. Primary sclerosing cholangitis: natural history, prognostic factors and survival analysis. Hepatology 1989;10(4):430-436.
Chronic
Alcohol
Ingestion
and Nutrition
Dear Sir: Korsten et al. state “the mean energy intake per rat in each group using our system of feeding was 230 kcal/kg per day, which is comparable to that consumed by animals pair-fed liquid diets of standard composition” (1). However, with the same liquid diet model, Lieber et al. claims a considerably greater amount of energy intake (400 kcal/kg per day) (2). The reason for this discrepancy is unknown. Korsten et al. report that young growing rats in group III of their study consumed a nutritionally adequate diet with ethanol for 28 days, and their body weight change was -1.7% ? 7.5% (1). How can the diet be nutritionally adequate if when fed, young rats did not grow? Even when rats were fed the nutritionally adequate diet without alcohol (group IV), they gained only 29.5% ? 5.1%, which is meager compared with the growth of rats fed the various known nutritionally adequate diets. For example, a 120-g rat must weigh about 316 g after being fed the nutritionally adequate AINor NIH-07 diets for 28 days (3), causing an increase of about 163% in body weight. It is unfortunate that the nutritional inadequacy of the liquid ethanol diet model is not yet appreciated despite numerous investigations addressing this aspect in recent years (4). An understanding of the role of nutrition can only advance research and improve our knowledge of the effects of chronic alcohol consumption. G. ANANDARAO, PHD. EDWARD C. LARKIN, M.D.
Alcohol Research Laboratory [151H) VeteransAdministration Medical Center 150 Muir Road Martinez, California 94553
1. Korsten MA, Wilson JS, Lieber CS. Interactive effects of dietary protein and ethanol on rat pancreas. Gastroenterology 1990;99: 229-236. 2. Lieber CS, DeCarli LM, Sorrel1 MF. Experimental methods of ethanol administration. Hepatology 1989;10:501-510.
295
3. Bieri JG, Stoewsand GS, Briggs GM, Phillips RW, Woodard JC, Knapka JJ. Report of the American Institute of Nutrition Ad Hoc Committee on standards for nutritional studies. J Nutr 1977;107: 1340-1348. 4. Rao GA, Larkin EC, Derr RF. Effects of chronic alcohol ingestion: role of nutritional factors. Biochem Arch 1989:5:289-296. Reply. The energy intake of rats using the Lieber-DeCarli liquid diet technique will necessarily vary according to study design and purpose. In our recent publication (l), we investigated the combined effects of protein deficiency and ethanol intake on pancreatic function. Inasmuch as protein-deficient rats fed ethanol were generally poor eaters, the mean energy consumption of rats in groups II, III, and N (protein deficient without ethanol, protein sufficient with ethanol, and protein sufficient without ethanol, respectively) was in the low range of normal and was not as high as that observed in less restrictive settings (2). However, by matching the overall caloric intake of groups II-IV with that consumed by the rats fed ethanol with protein-deficient diets (group I), we were able to study the role of protein deficiency without the confounding effects of differences in energy intake. Growth retardation was apparent in our rats despite feeding of protein-sufficient diets, probably as a consequence of restriction in nutrient intake. Despite slower rates of growth, however, animals receiving protein-sufficient diets (group IV) appeared healthy and did not show pathological changes at death. The healthy appearance of these rats supports the concept that moderate undernutrition without malnutrition is not detrimental. There is, in fact, experimental evidence that such a stage may actually be more favorable than ad libitum nutrition. This has been noted in relationship to bone composition (3) longevity (4) and susceptibility to disease (5), including spontaneously occurring neoplasms (6) and tumors secondary to radiation (7). Finally, notwithstanding our long-term interest in the direct toxicity of ethanol, we also are exploring the effects of nutrition on alcohol-induced pathology; hence the present study. The liquid diet technique permitted us to study the role of one nutritional factor, namely dietary protein, in a controlled and reproducible manner. MARKA. KORSTEN,M.D. JEREMYS. WILSON,M.D. CHARLES S. LIEBER, M.D.
Veterans Administration Medical Center I 151 G 130 West Kingsbridge Road Bronx, New York 10468-3994
1. Korsten MA, Wilson JS, Lieber CS. Interactive effects of dietary protein and ethanol on rat pancreas. Gastroenterology 1990;99: 229-236. 2. Lieber CS, DeCarli LM, Sorrel1 MF. Experimental methods of ethanol administration. Hepatology 1989;10:501-510. 3. Saville PD, Lieber CS. Increases in skeletal calcium and femur cortex thickness produced by undernutrition. Nutr 1969;99:141144. 4. 5.
6. 7.
Barrows CH. Nutrition, aging, and genetic program. Am J Clin Nutr 1972;25:829-833. Yu BP, Masoro EJ, Murata I, Bertrand HA and Lynd FT. Life span of SPF Fischer 344 male rats fed ad libitum or restricted diets. J Gerontol 1982;37:130-141. Weindruch R, Walford RL. Dietary restriction in mice beginning a 1 year of age. Science 1982;215:1415-1418. Gross L, Dreyfuss Y. Reduction in the incidence of radiationinduced tumors in rats after restriction of food intake. Proc Nat1 Acad Sci USA 1984;81:7596-7598.