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Gastrointestinal permeability in celiac disease
GASTROENTEROLOGY 1998;114:226–230
CORRESPONDENCE Readers are encouraged to write letters to the editor concerning articles that have been published in GASTROENTEROLOGY. Short, general comments are also considered, but use of the Correspondence section for publication of original data in preliminary form is not encouraged. Letters should be typewritten double-spaced and submitted in triplicate.
Gastrointestinal Permeability in Celiac Disease Dear Sir: We read with interest the recent paper by Smecuol et al.1 on gastrointestinal permeability in celiac disease. We concur with their opinion that increased sucrose permeability is a typical feature of untreated celiac disease. Indeed, their study showed the same results as ours earlier.2 However, interpretation of the data was highly dissimilar. In general, sucrose permeability test is considered a good marker of gastric damage,3 because this sugar is rapidly degraded in the small bowel by dissacharidases. In contrast to this notion, Smecuol et al. believe that increased sucrose permeability in celiac disease reflects damage of the upper small intestine rather than the stomach because decreased dissacharidase activity of the small bowel in active celiac disease delays sucrose degradation. Thus, sucrose may permeate through the small bowel, indicating duodenal and jejunal rather than gastric damage. Although this assumption is logical, it has not been proven. We want to draw attention to two facts. First, we found a significant correlation of sucrose permeability with an increase in the number of gastric intraepithelial lymphocytes (IELs).2 Second, we have shown in our study that duodenal administration of the sucrose test in celiac disease resulted in unequivocal decrease of urinary sugar excretion. Our first point may provide an explanation for increased gastric permeability, although it is not a proof. It is well known that patients with active celiac disease show an increase not only in intestinal but also in gastric IELs.4 We have found that 55% of the patients fulfill the criteria of lymphocytic gastritis (.25 IELs/100 epithelial cells) in the antrum and 50% in the body (Oberhuber et al., manuscript submitted). Furthermore, 90% show an increase in IELs of more than the mean 1 2 3 SD of the controls. These data are in clear contrast to the findings by Smecuol et al. shown in Figure 5, in which only 1 case of lymphocytic gastritis (of 27) is depicted. In our opinion, the number of gastric IELs, which may be difficult to detect in H&E sections, has been underestimated by Smecuol et al. We therefore recommend that the investigators perform immunohistochemical staining with anti-CD3 antibodies, which highlight IELs. Our second point shows that small bowel damage is neither the sole nor the main culprit for increased sucrose permeability. If the assumption of Smecuol et al. had been true, urinary sucrose excretion should have remained essentially the same after direct administration of the sugar into the duodenum, which was not the case in our study. Further, the rapid response of sucrose permeability to gluten-free diet is accompanied by disappearance of symptoms, especially gastric symptoms. Early rebiopsies never show completely normal duodenal mucosa (grade 0), but often normal mucosa in the stomach. This fact supports the notion that normalization of sucrose permeability and of gastric histology are interrelated. On the other hand, the authors introduce a new proximal distal gradient of gastrointestinal damage calculated as a sucrose/lactulose ratio. They speculate that it rapidly decreases after initiation of a gluten-free diet because more distal intestinal lesions remain, whereas
proximal intestinal lesions resolve. Two notions militate against this assumption. First, it has been known for a long time that duodenal/ jejunal damage is much more severe than ileal damage. Second, it has never been shown that ileal mucosa responds less well to gluten-free diet than duodenal/jejunal mucosa. We therefore favor the following interpretation: gastric mucosa responds more rapidly to gluten-free diet than duodenal/jejunal mucosa (unpublished results). This leads to normalization of sucrose permeability but not lactulose permeability. In our opinion, the sucrose test itself is not very promising for follow-up (which was also stated by Smecuol et al.) because it normalizes too fast (within 2 months) and before intestinal changes of celiac disease could have disappeared. GEORG OBERHUBER, M.D. Department of Clinical Pathology HARALD VOGELSANG, M.D. Department of Internal Medicine IV University of Vienna Medical School Vienna, Austria 1. Smecuol E, Bai JC, Vazquez H, et al. Gastrointestinal permeability in celiac disease. Gastroenterology 1997;112:1129–1136. 2. Vogelsang H, Oberhuber G, Wyatt J. Lymphocytic gastritis and gastric permeability in patients with celiac disease. Gastroenterology 1996;111:73–77. 3. Meddings JB, Sutherland LR, Byles NI, et al. Sucrose: a novel permeability marker for gastroduodenal disease [see comments]. Gastroenterology 1993;104:1619–1626. 4. Wolber R, Owen D, DelBuono L, et al. Lymphocytic gastritis in patients with celiac sprue or spruelike intestinal disease. Gastroenterology 1990;98:310–315.
Improving Fecal Blood Testing Dear Sir: The recent publication of clinical guidelines and rationale for colorectal cancer screening were deliberate in encouraging fecal blood testing and were explicit in nominating colonoscopy as the investigative procedure of choice but, in my opinion, failed to explicitly recommend the preferred fecal blood test.1 There is a need to nominate the preferred testing method and to perform it reliably if the benefits of fecal blood testing are to be realized. Our laboratory conducts a self-referral program for screening the general community and incorporates several features that could improve the reliability of fecal blood testing. First, uncertainty about the testing options must be allayed. Bresalier2 indicated that immunologic testing for fecal blood required further development and trials if it is to be comparable to the Hemoccult test. This implied that the use of Hemoccult was the reason that Mandel et al.3 showed a reduction in mortality when, in fact, it was fecal blood testing itself. I believe that, under the controlled testing conditions operating in that study, any reliable fecal occult blood test would have produced a similar result. The supporting argument for immunologic testing is based on its recognized specificity and sensitivity and on favorable comparisons with chemical methods.4–6 Despite this, immunologic testing has not been widely
January 1998
adopted because of its cost and because it cannot be easily performed in a physician’s office. If these detractions can be overcome, then the immunologic test should be the test of choice for screening the general community. There are valid arguments for separating the testing of a symptomatic patient with a fecal occult blood test and using such a test for screening for colorectal cancer. In the first instance, the test is for confirmation and only one sample may be conveniently tested. A chemical slide used in a physician’s office and tested at that site is appropriate and convenient. With screening, a more sensitive test is required and testing should be performed on three samples. In this instance, an immunologic test should be used and testing should be performed in a laboratory. The physician should receive the report of the screen but is not involved with the actual testing. In our screening program, the participant initiates the test and receives the report, but 85% of participants elect that their physicians shall also receive a report. In the article by Allison et al.7 that was reviewed by Bresalier, the cost of immunologic testing was sixfold of that of chemical testing and was due to high labor costs for processing specimens and conducting assays. Automated procedures are now available that perform these assays reliably and inexpensively. We currently use an automated enzyme-linked immunosorbent assay method for the immunologic testing for blood in feces, with the reagent cost comparable to that of a chemical test, and we have designed a better specimen collection system to reduce processing costs. Furthermore, interpretive error is minimized by programming the instrument to automatically report a positive test once the analytical response is above a defined cutoff value. Stability is another concern in fecal blood testing because the globin portion of hemoglobin is particularly degradable. Fecal smears become dehydrated on paper slides, and this stabilizes the hemoglobin. In Australia, 95% of the fecal samples arrive unstabilized to the laboratory because of practicable and financial reasons, and this practice has been criticized.8 Allison et al.7 punched fecal samples from a paper slide for immunologic testing but commented that the participants did not prepare these slides well. Our screening program now uses a sampling system in which the participant adds approximately 1 g of feces by a scoop to a tube containing a stabilizing solution. All subsequent steps are undertaken at the laboratory. Samples arrive in the laboratory ready for processing, and this fecal homogenate is used for an immunologic test or added to a chemical slide. The fecal homogenate is stable for several weeks. Using this liquid preparation in conjunction with quality controls, the reproducibility of testing has significantly improved. This sampling system is the basis for the posting of fecal specimens from anywhere in Australia. The unreliability of fecal blood testing can be caused by the methodology and performance by inexperienced individuals who conduct such tests infrequently. This can be compared with determining a serum glucose level with a dipstick when accurate methods are available in the laboratory. I have suggested solutions to some of the problems associated with fecal blood testing, which include using the best available testing procedure, the immunologic test; providing a collection device that is simple to use and enhances stability as well as facilitates the processing of the specimen; and introducing automation. This collective approach significantly reduces cost. However, to have a reliable screening program, all testing should be laboratory based, preferably centralized in dedicated laboratories, where other benefits can be incorporated into the screening program, namely,
CORRESPONDENCE
227
issuing reminder letters and collating statistics to evaluate the screening. After comparing three chemical fecal occult blood tests, Levin et al.9 pointed out that there is a need for a screening test with greater specificity and higher positive predictive value. The immunologic test offers this capability but needs to be automated to be cost-effective and reliable. Despite my criticisms that the guidelines do not go far enough, I nevertheless applaud their provision and the move to have screening funded under Medicare because this establishes directions that should be followed by other countries.10 JOHN B. EDWARDS Clinical Biochemistry Institute of Medical and Veterinary Science Adelaide, South Australia Australia 1. Colorectal cancer screening: clinical guidelines and rationale. Winawer SJ, Fletcher RH, Miller L, et al. Gastroenterology 1997; 112:594–642. 2. Bresalier R. Fecal occult blood testing: beyond Hemoccult. Gastroenterology 1997;112:664–665. 3. Mandel JS, Bond JH, Church TR, et al. Reducing mortality from colorectal cancer by screening for fecal occult blood. N Engl J Med 1993;328:1365–1371. 4. St John DJB, Young GP, Alexeff MA, et al. Evaluation of new occult blood tests for detection of colorectal neoplasia. Gastroenterology 1993;104:1661–1668. 5. Petrelli N, Michalek AM, Freedman A, et al. Immunochemical versus guaiac occult blood stool tests: results of a community based screening program. Surg Oncol 1994;3:27–36. 6. Shimbo T, Glick HA, Eisenberg JM. Cost-effectiveness analysis of strategies for colorectal cancer screening in Japan. Int J Technol Assess Health Care 1994;10:359–375. 7. Allison JE, Tekawa IS, Ransom LJ, et al. A comparison of fecal occult blood tests for colorectal cancer screening. N Engl J Med 1996;334:155–159. 8. Young GP, Sinatra MA, St John DJB. Influence of delay in stool sampling on fecal occult blood test sensitivity. Clin Chem 1996; 42:1107–1108. 9. Levin B, Hess K, Johnson C. Screening for colorectal cancer: a comparison of 3 fecal occult blood tests. Arch Intern Med 1997;157:970–976. 10. Walsh JH. Gastroenterology News. Gastroenterology 1997;112: 679–680.
PET Scanning as a Diagnostic Tool in Wilson’s Disease Dear Sir: I read the article by Steindl et al.1 in which they describe cases of Wilson’s disease that would have been missed had only conventional screening tests been used. As with any relatively uncommon disorder, one must always have a clinical suspicion to arrive at a correct and, hopefully, treatable diagnosis. I wondered if the authors had or have access to positron emission tomography (PET). Decreased glucose utilization (using 2-deoxy-2-[18F]fluro-D-glucose) is typically seen in the basal ganglia, especially the lenticular nuclei, in Wilson’s disease.2 This is consistent with areas of copper deposition. We have also used this modality to assist in the exclusion of Wilson’s disease.3 Magnetic resonance imaging also characteristically shows involvement of the lenticular nuclei, thalamus, and caudate nuclei.4 It would be of great interest if the investigators could scan their patients and report the
CORRESPONDENCE Readers are encouraged to write letters to the editor concerning articles that have been published in GASTROENTEROLOGY. Short, general comments are also considered, but use of the Correspondence section for publication of original data in preliminary form is not encouraged. Letters should be typewritten double-spaced and submitted in triplicate.
Gastrointestinal Permeability in Celiac Disease Dear Sir: We read with interest the recent paper by Smecuol et al.1 on gastrointestinal permeability in celiac disease. We concur with their opinion that increased sucrose permeability is a typical feature of untreated celiac disease. Indeed, their study showed the same results as ours earlier.2 However, interpretation of the data was highly dissimilar. In general, sucrose permeability test is considered a good marker of gastric damage,3 because this sugar is rapidly degraded in the small bowel by dissacharidases. In contrast to this notion, Smecuol et al. believe that increased sucrose permeability in celiac disease reflects damage of the upper small intestine rather than the stomach because decreased dissacharidase activity of the small bowel in active celiac disease delays sucrose degradation. Thus, sucrose may permeate through the small bowel, indicating duodenal and jejunal rather than gastric damage. Although this assumption is logical, it has not been proven. We want to draw attention to two facts. First, we found a significant correlation of sucrose permeability with an increase in the number of gastric intraepithelial lymphocytes (IELs).2 Second, we have shown in our study that duodenal administration of the sucrose test in celiac disease resulted in unequivocal decrease of urinary sugar excretion. Our first point may provide an explanation for increased gastric permeability, although it is not a proof. It is well known that patients with active celiac disease show an increase not only in intestinal but also in gastric IELs.4 We have found that 55% of the patients fulfill the criteria of lymphocytic gastritis (.25 IELs/100 epithelial cells) in the antrum and 50% in the body (Oberhuber et al., manuscript submitted). Furthermore, 90% show an increase in IELs of more than the mean 1 2 3 SD of the controls. These data are in clear contrast to the findings by Smecuol et al. shown in Figure 5, in which only 1 case of lymphocytic gastritis (of 27) is depicted. In our opinion, the number of gastric IELs, which may be difficult to detect in H&E sections, has been underestimated by Smecuol et al. We therefore recommend that the investigators perform immunohistochemical staining with anti-CD3 antibodies, which highlight IELs. Our second point shows that small bowel damage is neither the sole nor the main culprit for increased sucrose permeability. If the assumption of Smecuol et al. had been true, urinary sucrose excretion should have remained essentially the same after direct administration of the sugar into the duodenum, which was not the case in our study. Further, the rapid response of sucrose permeability to gluten-free diet is accompanied by disappearance of symptoms, especially gastric symptoms. Early rebiopsies never show completely normal duodenal mucosa (grade 0), but often normal mucosa in the stomach. This fact supports the notion that normalization of sucrose permeability and of gastric histology are interrelated. On the other hand, the authors introduce a new proximal distal gradient of gastrointestinal damage calculated as a sucrose/lactulose ratio. They speculate that it rapidly decreases after initiation of a gluten-free diet because more distal intestinal lesions remain, whereas
proximal intestinal lesions resolve. Two notions militate against this assumption. First, it has been known for a long time that duodenal/ jejunal damage is much more severe than ileal damage. Second, it has never been shown that ileal mucosa responds less well to gluten-free diet than duodenal/jejunal mucosa. We therefore favor the following interpretation: gastric mucosa responds more rapidly to gluten-free diet than duodenal/jejunal mucosa (unpublished results). This leads to normalization of sucrose permeability but not lactulose permeability. In our opinion, the sucrose test itself is not very promising for follow-up (which was also stated by Smecuol et al.) because it normalizes too fast (within 2 months) and before intestinal changes of celiac disease could have disappeared. GEORG OBERHUBER, M.D. Department of Clinical Pathology HARALD VOGELSANG, M.D. Department of Internal Medicine IV University of Vienna Medical School Vienna, Austria 1. Smecuol E, Bai JC, Vazquez H, et al. Gastrointestinal permeability in celiac disease. Gastroenterology 1997;112:1129–1136. 2. Vogelsang H, Oberhuber G, Wyatt J. Lymphocytic gastritis and gastric permeability in patients with celiac disease. Gastroenterology 1996;111:73–77. 3. Meddings JB, Sutherland LR, Byles NI, et al. Sucrose: a novel permeability marker for gastroduodenal disease [see comments]. Gastroenterology 1993;104:1619–1626. 4. Wolber R, Owen D, DelBuono L, et al. Lymphocytic gastritis in patients with celiac sprue or spruelike intestinal disease. Gastroenterology 1990;98:310–315.
Improving Fecal Blood Testing Dear Sir: The recent publication of clinical guidelines and rationale for colorectal cancer screening were deliberate in encouraging fecal blood testing and were explicit in nominating colonoscopy as the investigative procedure of choice but, in my opinion, failed to explicitly recommend the preferred fecal blood test.1 There is a need to nominate the preferred testing method and to perform it reliably if the benefits of fecal blood testing are to be realized. Our laboratory conducts a self-referral program for screening the general community and incorporates several features that could improve the reliability of fecal blood testing. First, uncertainty about the testing options must be allayed. Bresalier2 indicated that immunologic testing for fecal blood required further development and trials if it is to be comparable to the Hemoccult test. This implied that the use of Hemoccult was the reason that Mandel et al.3 showed a reduction in mortality when, in fact, it was fecal blood testing itself. I believe that, under the controlled testing conditions operating in that study, any reliable fecal occult blood test would have produced a similar result. The supporting argument for immunologic testing is based on its recognized specificity and sensitivity and on favorable comparisons with chemical methods.4–6 Despite this, immunologic testing has not been widely
January 1998
adopted because of its cost and because it cannot be easily performed in a physician’s office. If these detractions can be overcome, then the immunologic test should be the test of choice for screening the general community. There are valid arguments for separating the testing of a symptomatic patient with a fecal occult blood test and using such a test for screening for colorectal cancer. In the first instance, the test is for confirmation and only one sample may be conveniently tested. A chemical slide used in a physician’s office and tested at that site is appropriate and convenient. With screening, a more sensitive test is required and testing should be performed on three samples. In this instance, an immunologic test should be used and testing should be performed in a laboratory. The physician should receive the report of the screen but is not involved with the actual testing. In our screening program, the participant initiates the test and receives the report, but 85% of participants elect that their physicians shall also receive a report. In the article by Allison et al.7 that was reviewed by Bresalier, the cost of immunologic testing was sixfold of that of chemical testing and was due to high labor costs for processing specimens and conducting assays. Automated procedures are now available that perform these assays reliably and inexpensively. We currently use an automated enzyme-linked immunosorbent assay method for the immunologic testing for blood in feces, with the reagent cost comparable to that of a chemical test, and we have designed a better specimen collection system to reduce processing costs. Furthermore, interpretive error is minimized by programming the instrument to automatically report a positive test once the analytical response is above a defined cutoff value. Stability is another concern in fecal blood testing because the globin portion of hemoglobin is particularly degradable. Fecal smears become dehydrated on paper slides, and this stabilizes the hemoglobin. In Australia, 95% of the fecal samples arrive unstabilized to the laboratory because of practicable and financial reasons, and this practice has been criticized.8 Allison et al.7 punched fecal samples from a paper slide for immunologic testing but commented that the participants did not prepare these slides well. Our screening program now uses a sampling system in which the participant adds approximately 1 g of feces by a scoop to a tube containing a stabilizing solution. All subsequent steps are undertaken at the laboratory. Samples arrive in the laboratory ready for processing, and this fecal homogenate is used for an immunologic test or added to a chemical slide. The fecal homogenate is stable for several weeks. Using this liquid preparation in conjunction with quality controls, the reproducibility of testing has significantly improved. This sampling system is the basis for the posting of fecal specimens from anywhere in Australia. The unreliability of fecal blood testing can be caused by the methodology and performance by inexperienced individuals who conduct such tests infrequently. This can be compared with determining a serum glucose level with a dipstick when accurate methods are available in the laboratory. I have suggested solutions to some of the problems associated with fecal blood testing, which include using the best available testing procedure, the immunologic test; providing a collection device that is simple to use and enhances stability as well as facilitates the processing of the specimen; and introducing automation. This collective approach significantly reduces cost. However, to have a reliable screening program, all testing should be laboratory based, preferably centralized in dedicated laboratories, where other benefits can be incorporated into the screening program, namely,
CORRESPONDENCE
227
issuing reminder letters and collating statistics to evaluate the screening. After comparing three chemical fecal occult blood tests, Levin et al.9 pointed out that there is a need for a screening test with greater specificity and higher positive predictive value. The immunologic test offers this capability but needs to be automated to be cost-effective and reliable. Despite my criticisms that the guidelines do not go far enough, I nevertheless applaud their provision and the move to have screening funded under Medicare because this establishes directions that should be followed by other countries.10 JOHN B. EDWARDS Clinical Biochemistry Institute of Medical and Veterinary Science Adelaide, South Australia Australia 1. Colorectal cancer screening: clinical guidelines and rationale. Winawer SJ, Fletcher RH, Miller L, et al. Gastroenterology 1997; 112:594–642. 2. Bresalier R. Fecal occult blood testing: beyond Hemoccult. Gastroenterology 1997;112:664–665. 3. Mandel JS, Bond JH, Church TR, et al. Reducing mortality from colorectal cancer by screening for fecal occult blood. N Engl J Med 1993;328:1365–1371. 4. St John DJB, Young GP, Alexeff MA, et al. Evaluation of new occult blood tests for detection of colorectal neoplasia. Gastroenterology 1993;104:1661–1668. 5. Petrelli N, Michalek AM, Freedman A, et al. Immunochemical versus guaiac occult blood stool tests: results of a community based screening program. Surg Oncol 1994;3:27–36. 6. Shimbo T, Glick HA, Eisenberg JM. Cost-effectiveness analysis of strategies for colorectal cancer screening in Japan. Int J Technol Assess Health Care 1994;10:359–375. 7. Allison JE, Tekawa IS, Ransom LJ, et al. A comparison of fecal occult blood tests for colorectal cancer screening. N Engl J Med 1996;334:155–159. 8. Young GP, Sinatra MA, St John DJB. Influence of delay in stool sampling on fecal occult blood test sensitivity. Clin Chem 1996; 42:1107–1108. 9. Levin B, Hess K, Johnson C. Screening for colorectal cancer: a comparison of 3 fecal occult blood tests. Arch Intern Med 1997;157:970–976. 10. Walsh JH. Gastroenterology News. Gastroenterology 1997;112: 679–680.
PET Scanning as a Diagnostic Tool in Wilson’s Disease Dear Sir: I read the article by Steindl et al.1 in which they describe cases of Wilson’s disease that would have been missed had only conventional screening tests been used. As with any relatively uncommon disorder, one must always have a clinical suspicion to arrive at a correct and, hopefully, treatable diagnosis. I wondered if the authors had or have access to positron emission tomography (PET). Decreased glucose utilization (using 2-deoxy-2-[18F]fluro-D-glucose) is typically seen in the basal ganglia, especially the lenticular nuclei, in Wilson’s disease.2 This is consistent with areas of copper deposition. We have also used this modality to assist in the exclusion of Wilson’s disease.3 Magnetic resonance imaging also characteristically shows involvement of the lenticular nuclei, thalamus, and caudate nuclei.4 It would be of great interest if the investigators could scan their patients and report the