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Re: Oxentenko et al.—endoscopic markers in celiac disease
AJG – November, 2002
Letters to the Editor
that all bacteria identified by sequencing analysis were Gram-positive cocci. Of course, our findings do not provide clues to the actual role of Gram-positive cocci in the process of stone formation. However, considering that persons with cholesterol supersaturation of bile do not always develop cholesterol stones in the gallbladder, even though cholesterol supersaturation of bile is necessary for the formation of cholesterol stones (3), there must be additional factors, such as bacterial infection, that initiate or promote the formation of pure cholesterol stones. In fact, JaeWoon et al. have proposed that bile infection is associated with hypersecretion of mucin and that lipopolysaccharide from Escherichia coli stimulates mucin secretion from gallbladder epithelial cells (4). Moreover, it has been reported that hypersecretion of mucin, which promotes the nucleation of cholesterol crystals in bile, is regarded as an important factor in gallstone formation (5). Cariati and Cetta (1) insisted that the presence of Grampositive cocci in these gallstones is secondary to bacterial migration and it must be a contamination from bile. However, our newer data showed that bacteria in five gallstones differed from those in bile using DNA sequencing of polymerase chain reaction products (manuscript in preparation). Moreover, in six of 12 pure cholesterol stones, bacterial 16S ribosomal RNA was amplified only from the core portion of stones, not from bile in gallbladder. In another study, bacterial DNA was detected only in the core portions, and not from the surfaces of mixed cholesterol stones. Although further studies are necessary to clarify the biological roles of Gram-positive cocci in the formation of pure cholesterol stones, our data suggest that bacteria are not merely present in gallstones but play an important role on the formation of pure cholesterol stones. Manabu Kawai, M.D. Makoto Iwahashi, M.D. Kazuhisa Uchiyama, M.D. Hiroki Yamaue, M.D. Second Department of Surgery Wakayama Medical University School of Medicine Wakayama, Japan
REFERENCES 1. Cariati A, Cetta F. Re: Kawai et al.—Bacteria are not important in the formation of pure cholesterol stones. Am J Gastroenterol 2002;97:2921–2. 2. Kawai M, Iwahashi M, Uchiyama K, et al. Gram-positive cocci are associated with the formation of completely pure cholesterol stones. Am J Gastroenterol 2002;97:83– 8. 3. Carey MC, Small DM. The physical chemistry of cholesterol solubility in bile: Relationship to gallstone formation and dissolution in man. J Clin Invest 1978;61:998 –1026. 4. JaeWoon C, Klinkspoor JH, Tadashi Y, et al. Lipopolysaccharide from Escherichia coli stimulates mucin secretion by cultured dog gallbladder epithelial cells. Hepatology 1999;29: 1352–7. 5. Nunes DP, Afdhal NH, Offner GD. A recombinant bovine
2923
gallbladder mucin polypeptide binds biliary lipids and accelerates cholesterol crystal appearance time. Gastroenterology 1999;116:936 – 42.
Reprint requests and correspondence: Makoto Iwahashi, M.D., Second Department of Surgery, Wakayama Medical University, School of Medicine, 811-1, Kimiidera, Wakayama 641-8510, Japan. Received June 4, 2002; accepted July 31, 2002.
Re: Oxentenko et al.—Endoscopic Markers in Celiac Disease TO THE EDITOR: We read with great interest the paper by Oxentenko et al. (1) on endoscopic markers in celiac disease (CD). A total of 113 patients with iron deficiency anemia underwent a complete clinical and diagnostic workup that included upper GI tract endoscopy and four biopsies taken from the second and third parts of the duodenum, regardless of the endoscopic findings. Seventeen of these subjects fulfilled the histological criteria for a definite diagnosis of CD, and it is interesting that 10 of them came from the 18 with at least one of the endoscopic markers reported as suggestive of CD, whereas the other seven came from the 95 patients without any of the markers. These results indicate a sensitivity of 59%, a specificity of 92%, and positive and negative predictive values of respectively 56% and 93%, thus suggesting that duodenal endoscopic “markers” are unreliable in detecting patients with a high pretest probability of CD (i.e., those with iron deficiency anemia). The above results confirm the low sensitivity (50%), high specificity (99.6%), and weak positive predictive value (60%) of the loss of folds and the presence of a mosaic pattern and/or nodularity and scalloping in predicting CD. We found in a large series of patients with dyspepsia (2– 4). In this context, no additional data came from a recent study (5) in which endoscopic markers were re-evaluated including the duodenal bulb findings. Although overall diagnostic accuracy was 98.1%, 78 of the 367 patients (21.2%) were eventually diagnosed as celiacs, thus indicating a considerable selection bias. Finally, we would like to underline the usefulness of sampling the duodenal mucosa of all patients undergoing upper GI tract endoscopy for any of the symptoms possibly related to CD, regardless of the presence or absence of any macroscopic abnormality. Maria Teresa Bardella, M.D. Maurizio Quatrini, M.D. Dario Conte, M.D. Postgraduate School of Gastroenterology IRCCS Ospedale Maggiore Milano, Italy
2924
Letters to the Editor
REFERENCES 1. Oxentenko AS, Grisolano SW, Murray JA, et al. The insensitivity of endoscopic markers in celiac disease. Am J Gastroenterol 2002;97:933– 8. 2. Bardella MT, Minoli G, Radaelli F, et al. Reevaluation of duodenal endoscopic markers in the diagnosis of celiac disease. Gastrointest Endosc 2000;51:714 – 6. 3. Bardella MT, Minoli G, Ravizza D, et al. Increased prevalence of celiac disease in patients with dyspepsia. Arch Intern Med 2000;160:1489 –91. 4. Radaelli F, Minoli G, Bardella MT, et al. Celiac disease among patients referred for routine upper gastrointestinal endoscopy: Prevalence and diagnostic accuracy of duodenal endoscopic markers. Am J Gastroenterol 2000;95;1089 –90. 5. Brocchi E, Tomassetti P, Misitano B, et al. Endoscopic markers in adult coeliac disease. Dig Liv Dis 2002;34:177– 82.
Reprint requests and correspondence: Maria Teresa Bardella, M.D., Postgraduate School of Gastroenterology, IRCCS Ospedale Maggiore—Pad. Granelli, Via F. Sforza 35, 20122 Milano, Italy. Received May 20, 2002; accepted June 7, 2002.
Response to Drs. Bardella et al. TO THE EDITOR: We thank Bardella et al. (1) for their comments on our article (2) and completely agree with their recommendations for duodenal biopsy when indicated by clinical reason even when the mucosa appears normal. As many patients may undergo esophagogastroduodenoscopy without any clear indication for duodenal biopsy, such as gastroesophagea reflux disease or dysphagia, recognition of the endoscopic findings may allow a considerable number of celiacs to be identified by the astute observer. The prevalence of celiac disease in our series of patients with iron deficiency anemia was higher than that of the general population but would still be considered a moderate probability as compared with patients endoscoped for frank malabsorption in whom the sensitivity of endoscopic findings may be higher. It would behoove endoscopists to be aware that the unbiopsied duodenum may harbor undiagnosed celiac disease.
AJG – Vol. 97, No. 11, 2002
Reprint requests and correspondence: Joseph A. Murray, M.D., Mayo Clinic, Gastroenterology W19A, 200 First Street, S.W., Rochester, MN 55905. Received May 31, 2002; accepted June 7, 2002.
Re: Arguedas et al.—Hepatitis A Prevention Analysis TO THE EDITOR: We were pleased to see the hepatitis A prevention analysis presented by Arguedas et al. (1). Although several of their assumptions significantly differ from ours (2), both studies reach the same conclusion— targeted vaccination of chronic hepatitis C patients is acceptably cost-effective. Nonetheless, we believe Arguedas et al. (1) understate cost-effectiveness for two important reasons. First, the presumed annual infection rate of one per 10,000 is based on cases reported to local health authorities, ignoring that more than 75% of icteric infections are not reported (3). Further, although the analysis of targeted vaccination considers only those susceptible to hepatitis A, the incidence rate denominator includes susceptible and immune individuals. Because one third of Americans ⱖ40 yr have been previously infected (4), the infection rate among susceptible persons is 50% greater. Second, we are concerned by what we feel is inappropriate use of utility analysis. It is fitting to consider the quality of life decrement caused by hepatitis A, as its prevention is the focus of the study. However, applying utility values of 0.55– 0.95 to chronic hepatitis C implies it is less valuable to extend the lives of these versus healthier patients. By this logic, cost-effectiveness would be improved by withholding preventive medicine from persons with any condition that impairs quality of life, including the blind (utility score ⫽ 0.33) and depressed (utility score ⫽ 0.44) (5, 6). We believe outcomes research should begin with the premise that all lives are equally valuable, and only quality of life effects caused by the intervention assessed (both positive and negative) should be considered in cost-utility ratios. R. Jake Jacobs, M.P.A. Allen S. Meyerhoff, M.S. Capitol Outcomes Research Alexandria, Virginia
Amy Oxentenko, M.D. Jeffrey Alexander, M.D., F.A.C.P. Joseph A. Murray, M.D. Division of Gastroenterology and Hepatology Department of Internal Medicine Mayo Clinic Rochester, Minnesota
Raymond S. Koff, M.D. University of Massachusetts Medical School Worcester, Massachusetts
REFERENCES REFERENCES 1. Bardella MT, Quatrini M, Conte D. Re: Oxentenko et al.— Endoscopic markers in celiac disease. Am J Gastroenterol 2002; 97:2923– 4. 2. Oxentenko A, Grisolano SW, Murray JA, et al. Am J Gastroenterol 2002;97:933– 8.
1. Arguedas MR, Heudebert GR, Fallon MB, Stinnett AA. The cost-effectiveness of hepatitis A vaccination in patients with chronic hepatitis C viral infection in the United States. Am J Gastroenterol 2002;97:721– 8. 2. Jacobs RJ, Koff RS, Meyerhoff AS. The cost-effectiveness of vaccinating chronic hepatitis C patients against hepatitis A. Am J Gastroenterol 2002;97:427–34.
Letters to the Editor
that all bacteria identified by sequencing analysis were Gram-positive cocci. Of course, our findings do not provide clues to the actual role of Gram-positive cocci in the process of stone formation. However, considering that persons with cholesterol supersaturation of bile do not always develop cholesterol stones in the gallbladder, even though cholesterol supersaturation of bile is necessary for the formation of cholesterol stones (3), there must be additional factors, such as bacterial infection, that initiate or promote the formation of pure cholesterol stones. In fact, JaeWoon et al. have proposed that bile infection is associated with hypersecretion of mucin and that lipopolysaccharide from Escherichia coli stimulates mucin secretion from gallbladder epithelial cells (4). Moreover, it has been reported that hypersecretion of mucin, which promotes the nucleation of cholesterol crystals in bile, is regarded as an important factor in gallstone formation (5). Cariati and Cetta (1) insisted that the presence of Grampositive cocci in these gallstones is secondary to bacterial migration and it must be a contamination from bile. However, our newer data showed that bacteria in five gallstones differed from those in bile using DNA sequencing of polymerase chain reaction products (manuscript in preparation). Moreover, in six of 12 pure cholesterol stones, bacterial 16S ribosomal RNA was amplified only from the core portion of stones, not from bile in gallbladder. In another study, bacterial DNA was detected only in the core portions, and not from the surfaces of mixed cholesterol stones. Although further studies are necessary to clarify the biological roles of Gram-positive cocci in the formation of pure cholesterol stones, our data suggest that bacteria are not merely present in gallstones but play an important role on the formation of pure cholesterol stones. Manabu Kawai, M.D. Makoto Iwahashi, M.D. Kazuhisa Uchiyama, M.D. Hiroki Yamaue, M.D. Second Department of Surgery Wakayama Medical University School of Medicine Wakayama, Japan
REFERENCES 1. Cariati A, Cetta F. Re: Kawai et al.—Bacteria are not important in the formation of pure cholesterol stones. Am J Gastroenterol 2002;97:2921–2. 2. Kawai M, Iwahashi M, Uchiyama K, et al. Gram-positive cocci are associated with the formation of completely pure cholesterol stones. Am J Gastroenterol 2002;97:83– 8. 3. Carey MC, Small DM. The physical chemistry of cholesterol solubility in bile: Relationship to gallstone formation and dissolution in man. J Clin Invest 1978;61:998 –1026. 4. JaeWoon C, Klinkspoor JH, Tadashi Y, et al. Lipopolysaccharide from Escherichia coli stimulates mucin secretion by cultured dog gallbladder epithelial cells. Hepatology 1999;29: 1352–7. 5. Nunes DP, Afdhal NH, Offner GD. A recombinant bovine
2923
gallbladder mucin polypeptide binds biliary lipids and accelerates cholesterol crystal appearance time. Gastroenterology 1999;116:936 – 42.
Reprint requests and correspondence: Makoto Iwahashi, M.D., Second Department of Surgery, Wakayama Medical University, School of Medicine, 811-1, Kimiidera, Wakayama 641-8510, Japan. Received June 4, 2002; accepted July 31, 2002.
Re: Oxentenko et al.—Endoscopic Markers in Celiac Disease TO THE EDITOR: We read with great interest the paper by Oxentenko et al. (1) on endoscopic markers in celiac disease (CD). A total of 113 patients with iron deficiency anemia underwent a complete clinical and diagnostic workup that included upper GI tract endoscopy and four biopsies taken from the second and third parts of the duodenum, regardless of the endoscopic findings. Seventeen of these subjects fulfilled the histological criteria for a definite diagnosis of CD, and it is interesting that 10 of them came from the 18 with at least one of the endoscopic markers reported as suggestive of CD, whereas the other seven came from the 95 patients without any of the markers. These results indicate a sensitivity of 59%, a specificity of 92%, and positive and negative predictive values of respectively 56% and 93%, thus suggesting that duodenal endoscopic “markers” are unreliable in detecting patients with a high pretest probability of CD (i.e., those with iron deficiency anemia). The above results confirm the low sensitivity (50%), high specificity (99.6%), and weak positive predictive value (60%) of the loss of folds and the presence of a mosaic pattern and/or nodularity and scalloping in predicting CD. We found in a large series of patients with dyspepsia (2– 4). In this context, no additional data came from a recent study (5) in which endoscopic markers were re-evaluated including the duodenal bulb findings. Although overall diagnostic accuracy was 98.1%, 78 of the 367 patients (21.2%) were eventually diagnosed as celiacs, thus indicating a considerable selection bias. Finally, we would like to underline the usefulness of sampling the duodenal mucosa of all patients undergoing upper GI tract endoscopy for any of the symptoms possibly related to CD, regardless of the presence or absence of any macroscopic abnormality. Maria Teresa Bardella, M.D. Maurizio Quatrini, M.D. Dario Conte, M.D. Postgraduate School of Gastroenterology IRCCS Ospedale Maggiore Milano, Italy
2924
Letters to the Editor
REFERENCES 1. Oxentenko AS, Grisolano SW, Murray JA, et al. The insensitivity of endoscopic markers in celiac disease. Am J Gastroenterol 2002;97:933– 8. 2. Bardella MT, Minoli G, Radaelli F, et al. Reevaluation of duodenal endoscopic markers in the diagnosis of celiac disease. Gastrointest Endosc 2000;51:714 – 6. 3. Bardella MT, Minoli G, Ravizza D, et al. Increased prevalence of celiac disease in patients with dyspepsia. Arch Intern Med 2000;160:1489 –91. 4. Radaelli F, Minoli G, Bardella MT, et al. Celiac disease among patients referred for routine upper gastrointestinal endoscopy: Prevalence and diagnostic accuracy of duodenal endoscopic markers. Am J Gastroenterol 2000;95;1089 –90. 5. Brocchi E, Tomassetti P, Misitano B, et al. Endoscopic markers in adult coeliac disease. Dig Liv Dis 2002;34:177– 82.
Reprint requests and correspondence: Maria Teresa Bardella, M.D., Postgraduate School of Gastroenterology, IRCCS Ospedale Maggiore—Pad. Granelli, Via F. Sforza 35, 20122 Milano, Italy. Received May 20, 2002; accepted June 7, 2002.
Response to Drs. Bardella et al. TO THE EDITOR: We thank Bardella et al. (1) for their comments on our article (2) and completely agree with their recommendations for duodenal biopsy when indicated by clinical reason even when the mucosa appears normal. As many patients may undergo esophagogastroduodenoscopy without any clear indication for duodenal biopsy, such as gastroesophagea reflux disease or dysphagia, recognition of the endoscopic findings may allow a considerable number of celiacs to be identified by the astute observer. The prevalence of celiac disease in our series of patients with iron deficiency anemia was higher than that of the general population but would still be considered a moderate probability as compared with patients endoscoped for frank malabsorption in whom the sensitivity of endoscopic findings may be higher. It would behoove endoscopists to be aware that the unbiopsied duodenum may harbor undiagnosed celiac disease.
AJG – Vol. 97, No. 11, 2002
Reprint requests and correspondence: Joseph A. Murray, M.D., Mayo Clinic, Gastroenterology W19A, 200 First Street, S.W., Rochester, MN 55905. Received May 31, 2002; accepted June 7, 2002.
Re: Arguedas et al.—Hepatitis A Prevention Analysis TO THE EDITOR: We were pleased to see the hepatitis A prevention analysis presented by Arguedas et al. (1). Although several of their assumptions significantly differ from ours (2), both studies reach the same conclusion— targeted vaccination of chronic hepatitis C patients is acceptably cost-effective. Nonetheless, we believe Arguedas et al. (1) understate cost-effectiveness for two important reasons. First, the presumed annual infection rate of one per 10,000 is based on cases reported to local health authorities, ignoring that more than 75% of icteric infections are not reported (3). Further, although the analysis of targeted vaccination considers only those susceptible to hepatitis A, the incidence rate denominator includes susceptible and immune individuals. Because one third of Americans ⱖ40 yr have been previously infected (4), the infection rate among susceptible persons is 50% greater. Second, we are concerned by what we feel is inappropriate use of utility analysis. It is fitting to consider the quality of life decrement caused by hepatitis A, as its prevention is the focus of the study. However, applying utility values of 0.55– 0.95 to chronic hepatitis C implies it is less valuable to extend the lives of these versus healthier patients. By this logic, cost-effectiveness would be improved by withholding preventive medicine from persons with any condition that impairs quality of life, including the blind (utility score ⫽ 0.33) and depressed (utility score ⫽ 0.44) (5, 6). We believe outcomes research should begin with the premise that all lives are equally valuable, and only quality of life effects caused by the intervention assessed (both positive and negative) should be considered in cost-utility ratios. R. Jake Jacobs, M.P.A. Allen S. Meyerhoff, M.S. Capitol Outcomes Research Alexandria, Virginia
Amy Oxentenko, M.D. Jeffrey Alexander, M.D., F.A.C.P. Joseph A. Murray, M.D. Division of Gastroenterology and Hepatology Department of Internal Medicine Mayo Clinic Rochester, Minnesota
Raymond S. Koff, M.D. University of Massachusetts Medical School Worcester, Massachusetts
REFERENCES REFERENCES 1. Bardella MT, Quatrini M, Conte D. Re: Oxentenko et al.— Endoscopic markers in celiac disease. Am J Gastroenterol 2002; 97:2923– 4. 2. Oxentenko A, Grisolano SW, Murray JA, et al. Am J Gastroenterol 2002;97:933– 8.
1. Arguedas MR, Heudebert GR, Fallon MB, Stinnett AA. The cost-effectiveness of hepatitis A vaccination in patients with chronic hepatitis C viral infection in the United States. Am J Gastroenterol 2002;97:721– 8. 2. Jacobs RJ, Koff RS, Meyerhoff AS. The cost-effectiveness of vaccinating chronic hepatitis C patients against hepatitis A. Am J Gastroenterol 2002;97:427–34.