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Losing weight, but gaining gallstones (but maybe not)
800
SELECTED
SUMMARIES
does the molar percentage of phospholipids decrease? Of some interest is the finding that the percentage of lithocholate increases significantly in these patients; why does this occur and does it have anything to do with stone formation? Our studies (Gastroenterology 1988;94:A567] of stone formation in hamsters fed a high-carbohydrate, fat-free diet (not dissimilar to the diet the patients received!) have also shown that the percentage of biliary lithocholate increases significantly. Would a somewhat different diet, with the same total caloric value but differing proportions of carbohydrate and protein. produce a different effect on bile composition, as is the case with hamsters (Z Ernahrungswiss 1961;2:91-102)? Not examined, but clearly fertile ground for the future, is the role of gallbladder motility (stasis) during the diet. Neither the rate of weight loss nor the total amount of pounds shed seemed to be predictive of stone and crystal formation. Was there any parameter that might be predictive? The authors found that in stone/crystal formers, the CSI increased significantly, from the CSI 1.21 at entry to 1.42 by the fourth week. In nonformers. did not change (1.07 vs. 1.02). In the placebo group, however, the CSI at entry in stone/crystal formers rose significantly, from 1.22 to 1.45, and in nonformers, it also rose significantly, from 0.87 to 1.07. The entry CSI for stone/crystal formers in the placebo group (1.22) was significantly higher than in nonformers (0.87) as was the 4-wk CSI value. Further work will be needed to sort out which was more important in contributing to stone formation, the initially higher CSI or the magnitude of the increase in the CSI during the diet. The patients in the UDCA group received an average of 11.4 mg/kg day of UDCA. This is in the high-dosage range and would be quite sufficient to dissolve preexisting cholesterol stones. Would a lower dose of UDCA have produced the same preventive effect? How low a dose could be given before the preventive effect would be lost? The conclusions that can be drawn from the aspirin data are somewhat tentative, in my view. Yes, aspirin did seem to prevent stone and crystal formation to a similar statistical degree as UDCA. It was not clear to me, however, whether the results were significantly different from those in the placebo group. The dose of aspirin used, 1300 mg/day (four 325-mg tablets), seems somewhat high to use in clinical practice in otherwise healthy patients. Would a lower dose of aspirin have the same efficacy? The effect of UDCA plus aspirin would be a logical next step to examine, as would the question why the CSI did not increase in the aspirin group. These aspirin results are in concert with a recent report from the British/Belgian Gallstone Study Group (Lancet 1988; i:1223-5). This report noted that patients who had had successful stone dissolution using UDCA had a significantly lower stone recurrence rate if they were using nonsteroidal antiinflammatory drugs (for treatment of rheumatic complaints) than did patients who never or rarely used these drugs. As the authors of the current study conclude, further studies of aspirin are warranted. The results regarding the biliary glycoprotein content raise a few questions. The assay procedures referenced (Gastroenterology 1985;89:648-58, Biochim Biophys Acta 1982;706:221-8) involve sample dialysis, ultracentrifugation, column chromatography, CsCl gradient ultracentrifugation, and, finally, staining by the periodic acid-Schiff reaction. Using this technique, one can be fairly confident that mucin glycoproteins have been isolated with a good recovery rate. Why, then, did the authors not call the glycoproteins mucin glycoproteins, but simply glycoproteins? I am, therefore, not quite sure what class (size) glycoprotein is being affected by the aspirin (and UDCA); is it mucin or not? Second, the values reported for glycoprotein content (range 10.413.1 mgiml) seem quite high when compared with other reported values [for example, the report by Gallinger et al. (Gastroenterology 1987;92:867-75) of gallbladder bile total protein content in patients with cholesterol stones (mean 2.1 mgiml) and in controls
GASTROENTEROLOGY
Vol. 97. No. 3
(mean 1.48 mg/ml)]. I wonder if, in the current study, there may have been contamination of the samples obtained by the duodenal intubation technique with small bowel, gastric, or even salivary contents, thus elevating the values. This method of sample collection for protein measurements would appear to need further validation. The long-term follow-up in the 6 (nonoperated) patients with stones is quite interesting. No details of further treatment are given, but apparently in 3 patients, no stones or sludge could be detected. What happened to the stones? Are these false-negative ultrasound results or did the stones actually disappear? This seems to be another area for further study. I suppose the final relevant question is whether the results support the use of UDCA in patients undergoing such drastic diets. Certainly, one can say that its indiscriminant use by those not familiar with the drug is not recommended. The standard disclaimer applies that more research is needed before widespread use can be recommended. For those conversant with bile salts, however. the use of UDCA in such a setting (most fruitfully, in further scientific trials) seems worthwhile. P. F. MALET. M.U.
Reply. We agree that the conclusions
that can be drawn
from the
aspirin data are tentative. especially as the frequency of developing stones and crystals in the aspirin group was not statistically different from the frequency in either the placebo or urso group. The method we used for quantitating glycoproteins was chosen because it has been reported to be specific for mucin glycoproteins. and we have no reason to believe that we measured other types of glycoproteins. Nevertheless, we did not validate the specificity of the method for mucin glycoproteins ourselves and thus chose to use the term glycoproteins. The glycoprotein values we reported are indeed higher than those reported by some groups. Contamination with intestinal fluid (including mucin) is unavoidable when bile is obtained by duodenal biliary drainage and, by our estimates, causes an -30% dilution of the bile. This could elevate the glycoprotein values. Nevertheless, contamination should be (and was) relatively constant from drainage to drainage in individual patients. This may explain why we were able to show significant changes in glycoprotein and other values despite contamination. 1. W. MARKS, M.D. L. J. SCHOENFIELD, M.D. A. SILVERMAN, M.D.
RAF-l PROTEIN: A CYTOPLASMIC SIGNAL TRANSDUCING AGENT FOR PROLIFERATIVE STIMULI Morrison DK, Kaplan DR, Rapp LJ, et al. (Dana-Farber Cancer Institute and Department of Pathology, Harvard Medical School, Boston, Massachusetts). Signal transduction from membrane to cytoplasm: growth factors and membrane-bound oncogene products increase Raf-1 phosphorylation and associated protein kinase activity. Proc Nat1 Acad Sci USA 1988;85:8855-9 (December).
This study examined the effects of a variety of oncogenic transformations or mitogen treatment of mouse 3T3-fibroblast cells on the phosphorylation and activity of the cytoplasmic protein Raf-1, a product of the Raf-1 protooncogene. Raf-1 has been implicated in mitogenesis and
SELECTED
SUMMARIES
does the molar percentage of phospholipids decrease? Of some interest is the finding that the percentage of lithocholate increases significantly in these patients; why does this occur and does it have anything to do with stone formation? Our studies (Gastroenterology 1988;94:A567] of stone formation in hamsters fed a high-carbohydrate, fat-free diet (not dissimilar to the diet the patients received!) have also shown that the percentage of biliary lithocholate increases significantly. Would a somewhat different diet, with the same total caloric value but differing proportions of carbohydrate and protein. produce a different effect on bile composition, as is the case with hamsters (Z Ernahrungswiss 1961;2:91-102)? Not examined, but clearly fertile ground for the future, is the role of gallbladder motility (stasis) during the diet. Neither the rate of weight loss nor the total amount of pounds shed seemed to be predictive of stone and crystal formation. Was there any parameter that might be predictive? The authors found that in stone/crystal formers, the CSI increased significantly, from the CSI 1.21 at entry to 1.42 by the fourth week. In nonformers. did not change (1.07 vs. 1.02). In the placebo group, however, the CSI at entry in stone/crystal formers rose significantly, from 1.22 to 1.45, and in nonformers, it also rose significantly, from 0.87 to 1.07. The entry CSI for stone/crystal formers in the placebo group (1.22) was significantly higher than in nonformers (0.87) as was the 4-wk CSI value. Further work will be needed to sort out which was more important in contributing to stone formation, the initially higher CSI or the magnitude of the increase in the CSI during the diet. The patients in the UDCA group received an average of 11.4 mg/kg day of UDCA. This is in the high-dosage range and would be quite sufficient to dissolve preexisting cholesterol stones. Would a lower dose of UDCA have produced the same preventive effect? How low a dose could be given before the preventive effect would be lost? The conclusions that can be drawn from the aspirin data are somewhat tentative, in my view. Yes, aspirin did seem to prevent stone and crystal formation to a similar statistical degree as UDCA. It was not clear to me, however, whether the results were significantly different from those in the placebo group. The dose of aspirin used, 1300 mg/day (four 325-mg tablets), seems somewhat high to use in clinical practice in otherwise healthy patients. Would a lower dose of aspirin have the same efficacy? The effect of UDCA plus aspirin would be a logical next step to examine, as would the question why the CSI did not increase in the aspirin group. These aspirin results are in concert with a recent report from the British/Belgian Gallstone Study Group (Lancet 1988; i:1223-5). This report noted that patients who had had successful stone dissolution using UDCA had a significantly lower stone recurrence rate if they were using nonsteroidal antiinflammatory drugs (for treatment of rheumatic complaints) than did patients who never or rarely used these drugs. As the authors of the current study conclude, further studies of aspirin are warranted. The results regarding the biliary glycoprotein content raise a few questions. The assay procedures referenced (Gastroenterology 1985;89:648-58, Biochim Biophys Acta 1982;706:221-8) involve sample dialysis, ultracentrifugation, column chromatography, CsCl gradient ultracentrifugation, and, finally, staining by the periodic acid-Schiff reaction. Using this technique, one can be fairly confident that mucin glycoproteins have been isolated with a good recovery rate. Why, then, did the authors not call the glycoproteins mucin glycoproteins, but simply glycoproteins? I am, therefore, not quite sure what class (size) glycoprotein is being affected by the aspirin (and UDCA); is it mucin or not? Second, the values reported for glycoprotein content (range 10.413.1 mgiml) seem quite high when compared with other reported values [for example, the report by Gallinger et al. (Gastroenterology 1987;92:867-75) of gallbladder bile total protein content in patients with cholesterol stones (mean 2.1 mgiml) and in controls
GASTROENTEROLOGY
Vol. 97. No. 3
(mean 1.48 mg/ml)]. I wonder if, in the current study, there may have been contamination of the samples obtained by the duodenal intubation technique with small bowel, gastric, or even salivary contents, thus elevating the values. This method of sample collection for protein measurements would appear to need further validation. The long-term follow-up in the 6 (nonoperated) patients with stones is quite interesting. No details of further treatment are given, but apparently in 3 patients, no stones or sludge could be detected. What happened to the stones? Are these false-negative ultrasound results or did the stones actually disappear? This seems to be another area for further study. I suppose the final relevant question is whether the results support the use of UDCA in patients undergoing such drastic diets. Certainly, one can say that its indiscriminant use by those not familiar with the drug is not recommended. The standard disclaimer applies that more research is needed before widespread use can be recommended. For those conversant with bile salts, however. the use of UDCA in such a setting (most fruitfully, in further scientific trials) seems worthwhile. P. F. MALET. M.U.
Reply. We agree that the conclusions
that can be drawn
from the
aspirin data are tentative. especially as the frequency of developing stones and crystals in the aspirin group was not statistically different from the frequency in either the placebo or urso group. The method we used for quantitating glycoproteins was chosen because it has been reported to be specific for mucin glycoproteins. and we have no reason to believe that we measured other types of glycoproteins. Nevertheless, we did not validate the specificity of the method for mucin glycoproteins ourselves and thus chose to use the term glycoproteins. The glycoprotein values we reported are indeed higher than those reported by some groups. Contamination with intestinal fluid (including mucin) is unavoidable when bile is obtained by duodenal biliary drainage and, by our estimates, causes an -30% dilution of the bile. This could elevate the glycoprotein values. Nevertheless, contamination should be (and was) relatively constant from drainage to drainage in individual patients. This may explain why we were able to show significant changes in glycoprotein and other values despite contamination. 1. W. MARKS, M.D. L. J. SCHOENFIELD, M.D. A. SILVERMAN, M.D.
RAF-l PROTEIN: A CYTOPLASMIC SIGNAL TRANSDUCING AGENT FOR PROLIFERATIVE STIMULI Morrison DK, Kaplan DR, Rapp LJ, et al. (Dana-Farber Cancer Institute and Department of Pathology, Harvard Medical School, Boston, Massachusetts). Signal transduction from membrane to cytoplasm: growth factors and membrane-bound oncogene products increase Raf-1 phosphorylation and associated protein kinase activity. Proc Nat1 Acad Sci USA 1988;85:8855-9 (December).
This study examined the effects of a variety of oncogenic transformations or mitogen treatment of mouse 3T3-fibroblast cells on the phosphorylation and activity of the cytoplasmic protein Raf-1, a product of the Raf-1 protooncogene. Raf-1 has been implicated in mitogenesis and