Letters to the Editor
nature publishing group
4. Committee On Quality Of Health Care In A, Medicine I. Crossing the Quality Chasm: A New Health System for the 21st Century National Academies Press; 2001.
1
Division of Gastroenterology, University of Michigan, Ann Arbor Michigan, USA; 2Division of Gastroenterology, Northwestern University, Chicago, Illinois, USA. Correspondence: Neehar D. Parikh, MD, MS, Division of Gastroenterology, University of Michigan, 3912 Taubman Center, 1500 E Medical Center Dr, Ann Arbor, Michigan 48104, USA. E-mail: [email protected]
Immortal Time Bias: A Likely Alternate Explanation for the Purported Benefits of DXA Screening in Ulcerative Colitis Laura E. Targownik, MD, MSHS1 doi:10.1038/ajg.2014.234
To the Editor: We have read with interest your recent article in the April 2014 issue of the American College of Gastroenterology entitled “Adherence and Efficacy of Screening for Low Bone Mineral Density Among Ulcerative Colitis Patients Treated With Corticosteroids” (1). In this study, Khan et al. (1) aimed to evaluate the role of dual-energy X-ray absorptiometry (DXA) screening for preventing the occurrence of fracture in persons who have received corticosteroids for the treatment of ulcerative colitis. The authors report, somewhat surprisingly, that merely undergoing a DXA is associated with a 50% reduction in the risk for subsequent fracture, independent of the results or any specific intervention based on the DXA findings. Unfortunately, it is likely that the purported benefits of this manuscript are the result of immortal time bias (2,3). Immortal time bias occurs when person-time is accrued among members of a treated or screened cohort during which time the adverse event of interest cannot occur. © 2014 by the American College of Gastroenterology
Furthermore, if the adverse events were to occur in this time period, it would be counted against the untreated or unscreened group. Therefore, it is important for researchers to be aware of immortal time bias when performing time-to-event analyses, as this may give the erroneous appearance of benefit, particularly in studies involving drug therapies or screening tests. In this study, the issue of concern is how the person-time accumulated between the date of the initial prescription of corticosteroids (the condition for cohort entry) and the date of the DXA (for the DXA cohort) is “immortal”, in the sense that every person who receives a DXA is obliged to be alive and fracture free for this period. If this person-time is counted in the denominator of the DXA-exposed group, it falsely deflates the incidence rate of events in the DXA-based group. In this study, as the average time between corticosteroid prescription and DXA is just under 3 years, and the average total follow-up time is around 6 years, the incidence rate is probably underestimated by 50% (an amount roughly equivalent to the stated benefits). It would be greatly appreciated if you could let us know whether and how you accounted for immortal time bias, and, if not, would you be willing to rerun this analysis taking this unaccounted persontime into your calculations. This is most commonly performed by treating the intervention (DXA) as a time-dependent covariate (2). CONFLICT OF INTEREST The author declares no conflict of interest.
REFERENCES 1. Khan N, Abbas AM, Almukhtar RM et al. Adherence and efficacy of screening for low bone mineral density among ulcerative colitis patients treated with corticosteroids. Am J Gastroenterol 2014;109:572–8. 2. Suissa S. Immortal time bias in pharmaco-epidemiology. Am J Epidemiol 2008;167:492–9. 3. Rothman KJ, Suissa S.. Exclusion of immortal person-time. Pharmacoepidemiol Drug Saf 2008;17:1036. 1
Department of Gastroenterology, University of Manitoba, Winnipeg, Manitoba, Canada. Correspondence: Laura E. Targownik, MD, MSHS, Department of Biochemistry, University of Otago, 710 Cumberland Street, Dunedin, Otago 9054, New Zealand. E-mail: [email protected]
Polypectomy to Eradicate Cap Polyposis With Protein-Losing Enteropathy Yoshiaki Arimura, MD, PhD1, Hiroyuki Isshiki, MD1, Daisuke Hirayama, MD1, Kei Onodera, MD1, Kayo Murakami, MD1, Kentaro Yamashita, MD, PhD1 and Yasuhisa Shinomura, MD, PhD1 doi:10.1038/ajg.2014.227
To the Editor: Cap polyposis is a rare disease characterized by mucoid, bloody diarrhea, and polyps covered by a cap of fibrinopurulent mucous. Neither optimal treatment nor the etiology has been established. Polyp removal appears to provide only temporary relief (1), although cure is possible in patients with solitary lesions (2). We herein describe a patient with extensive cap polyposis whose disorganized tight junctions led to the manifestation of protein-losing enteropathy. The patient’s condition was successfully eradicated by polypectomy. A 43-year-old man was referred to our university hospital because of intractable bloody diarrhea and hypoproteinemia. Upon admission, he was seen to have been experiencing 12 bowel movements a day with straining, and exhibited moderate pitting edema extending up to both knees. Blood tests revealed a total protein level of 5.1 g/dl, an albumin level of 2.2 g/dl, and severe anemia with a hemoglobin concentration of 8.7 g/dl. Approximately 500 polyps involving the entire colon, excluding the cecum and ascending colon (Figure 1a), were removed by seven polypectomy procedures (Figure 1b). The total protein, albumin, and hemoglobin levels recovered to the reference ranges, and the diarrhea disappeared. No signs of polyp recurrence were present 1 year after the first visit (6 months after the last polypectomy). The two novel findings in this case are that polypectomy with curative intent can be safe and minimally invasive and that the polyps in patients with cap polyposis can be “leaky.” The American Journal of GASTROENTEROLOGY
1689
1690
Letters to the Editor
nature publishing group
Figure 1. Colonoscopic images and immunofluorescent analysis. (a) Initial colonoscopic image at the hepatic flexure, in which the polyps were most densely located. (b) Last colonoscopic image after seven polypectomy procedures at the same portion of the panel a.
Figure 2. Immunofluorescence analysis of tight junctions. Claudin-2 in the polyp epithelia (a) and normal colonic epithelia (b) in the present case. Claudin-7 in the polyp epithelia (c) and normal colonic epithelia (d) in the present case. The slides are viewed under a confocal microscope (LSM 510 META ConfoCor 3; Carl Zeiss, Oberkochen, Germany). Excitation at 543 nm induced Alexa Fluor 488 fluorescence (green emission) for claudin-2 and -7, whereas excitation at 364 nm induced 4,6-diamidino-2-phenylindole fluorescence of nuclei (blue emission).
Our patient underwent multiple polypectomy procedures with no serious complications or signs of recurrence throughout The American Journal of GASTROENTEROLOGY
a 1-year observation period. These findings suggest that the currently established recommendations are based on anecdo-
tal evidence: polypectomy is indicated for fewer than 10 polyps (1,2), whereas surgical resection is required for greater numbers of polyps. In addition, there is reportedly a potentially increased risk for postpolypectomy bleeding in such cases. As polyposis can recur even after proctocolectomy (3), semitotal colectomy, which would be inevitable to treat our patient, is not always curable. Such devastating surgery seems unrealistic, but minimally invasive polypectomy seems preferable for the benign nature of the disease. We also found that the polyps in cap polyposis can be “leaky.” We believe that, when cap polyposis manifests as protein-losing enteropathy, serum proteins are exclusively lost from the fibrinopurulent cap at the tip of the polyps because of the absence of epithelial barriers. Surprisingly, the barrier integrity of the polyps in our patients was broadly impaired even in the intact, covered epithelia, in which pore-forming claudin-2 was abnormally upregulated and redistributed (Figure 2a and b) (4). Conversely, the levels of pore-sealing claudin-7 were downregulated in our patient (Figure 2c and d). In the large intestine, claudin-2 is only detected in the deep crypts by expression in gradients along the crypt-to-villous axis (5), whereas claudin-7 is expressed more strongly on basolateral surfaces of the intestinal epithelium than on the apical tips (6). Tight junctions are the most apical junctional complex backboned by claudins. The perturbation of claudins compellingly suggests that extensive polypectomy is an effective and preferable treatment option for cap polyposis. In conclusion, we have described a patient with extensive cap polyposis that manifested as protein-losing enteropathy, which was successfully treated by definitive polypectomy. Establishment of optimal management protocols for gastrointestinal polyposis syndromes such as cap polyposis is urgently needed. ACKNOWLEDGMENTS We are very grateful to E. Katahira at the Department of Gastroenterology, Rheumatology, and Clinical Immunology, for providing technical assistance. CONFLICT OF INTEREST Guarantor of the article: Yoshiaki Arimura, MD, PhD. VOLUME 109 | OCTOBER 2014 www.amjgastro.com
Letters to the Editor
nature publishing group
Specific author contributions: All authors had access to the data, had a role in the writing of the manuscript, and approved the final version for submission. Financial support: None. Potential competing interests: None. REFERENCES 1. Akamatsu T, Nakamura N, Kawamura Y et al. Possible relationship between Helicobacter pylori infection and cap polyposis of the colon. Helicobacter 2004;9:651–6.
© 2014 by the American College of Gastroenterology
2. Ng K-H, Mathur P, Kumarasinghe MP et al. Cap polyposis: further experience and review. Dis Colon Rectum 2004;47:1208–15. 3. Konishi T, Watanabe T, Takei Y et al. Confined progression of cap polyposis along the anastomotic line, implicating the role of inflammatory responses in the pathogenesis. Gastrointest Endosc 2005;62:446–7. 4. Furuse M, Furuse K, Sasaki H et al. Conversion of zonulae occludentes from tight to leaky strand type by introducing claudin-2 into Madin-Darby canine kidney I cells. J Cell Biol 2001;153:263–72. 5. Chiba H, Osanai M, Murata M et al. Transmembrane proteins of tight junctions. Biochim Biophys Acta 2008;1778:588–600.
6. Fujita H, Chiba H, Yokozaki H et al. Differential expression and subcellular localization of claudin-7, -8, -12, -13, and -15 along the mouse intestine. J Histochem Cytochem 2006;54: 933–44. 1
Department of Gastroenterology, Rheumatology, and Clinical Immunology, Sapporo Medical University, Sapporo, Japan. Correspondence: Yoshiaki Arimura, MD, PhD, Department of Gastroenterology, Rheumatology, and Clinical Immunology, Sapporo Medical University, S-1, W-16, Chuo-ku, Sapporo 060-8543, Japan. E-mail: [email protected]
The American Journal of GASTROENTEROLOGY
1691
nature publishing group
4. Committee On Quality Of Health Care In A, Medicine I. Crossing the Quality Chasm: A New Health System for the 21st Century National Academies Press; 2001.
1
Division of Gastroenterology, University of Michigan, Ann Arbor Michigan, USA; 2Division of Gastroenterology, Northwestern University, Chicago, Illinois, USA. Correspondence: Neehar D. Parikh, MD, MS, Division of Gastroenterology, University of Michigan, 3912 Taubman Center, 1500 E Medical Center Dr, Ann Arbor, Michigan 48104, USA. E-mail: [email protected]
Immortal Time Bias: A Likely Alternate Explanation for the Purported Benefits of DXA Screening in Ulcerative Colitis Laura E. Targownik, MD, MSHS1 doi:10.1038/ajg.2014.234
To the Editor: We have read with interest your recent article in the April 2014 issue of the American College of Gastroenterology entitled “Adherence and Efficacy of Screening for Low Bone Mineral Density Among Ulcerative Colitis Patients Treated With Corticosteroids” (1). In this study, Khan et al. (1) aimed to evaluate the role of dual-energy X-ray absorptiometry (DXA) screening for preventing the occurrence of fracture in persons who have received corticosteroids for the treatment of ulcerative colitis. The authors report, somewhat surprisingly, that merely undergoing a DXA is associated with a 50% reduction in the risk for subsequent fracture, independent of the results or any specific intervention based on the DXA findings. Unfortunately, it is likely that the purported benefits of this manuscript are the result of immortal time bias (2,3). Immortal time bias occurs when person-time is accrued among members of a treated or screened cohort during which time the adverse event of interest cannot occur. © 2014 by the American College of Gastroenterology
Furthermore, if the adverse events were to occur in this time period, it would be counted against the untreated or unscreened group. Therefore, it is important for researchers to be aware of immortal time bias when performing time-to-event analyses, as this may give the erroneous appearance of benefit, particularly in studies involving drug therapies or screening tests. In this study, the issue of concern is how the person-time accumulated between the date of the initial prescription of corticosteroids (the condition for cohort entry) and the date of the DXA (for the DXA cohort) is “immortal”, in the sense that every person who receives a DXA is obliged to be alive and fracture free for this period. If this person-time is counted in the denominator of the DXA-exposed group, it falsely deflates the incidence rate of events in the DXA-based group. In this study, as the average time between corticosteroid prescription and DXA is just under 3 years, and the average total follow-up time is around 6 years, the incidence rate is probably underestimated by 50% (an amount roughly equivalent to the stated benefits). It would be greatly appreciated if you could let us know whether and how you accounted for immortal time bias, and, if not, would you be willing to rerun this analysis taking this unaccounted persontime into your calculations. This is most commonly performed by treating the intervention (DXA) as a time-dependent covariate (2). CONFLICT OF INTEREST The author declares no conflict of interest.
REFERENCES 1. Khan N, Abbas AM, Almukhtar RM et al. Adherence and efficacy of screening for low bone mineral density among ulcerative colitis patients treated with corticosteroids. Am J Gastroenterol 2014;109:572–8. 2. Suissa S. Immortal time bias in pharmaco-epidemiology. Am J Epidemiol 2008;167:492–9. 3. Rothman KJ, Suissa S.. Exclusion of immortal person-time. Pharmacoepidemiol Drug Saf 2008;17:1036. 1
Department of Gastroenterology, University of Manitoba, Winnipeg, Manitoba, Canada. Correspondence: Laura E. Targownik, MD, MSHS, Department of Biochemistry, University of Otago, 710 Cumberland Street, Dunedin, Otago 9054, New Zealand. E-mail: [email protected]
Polypectomy to Eradicate Cap Polyposis With Protein-Losing Enteropathy Yoshiaki Arimura, MD, PhD1, Hiroyuki Isshiki, MD1, Daisuke Hirayama, MD1, Kei Onodera, MD1, Kayo Murakami, MD1, Kentaro Yamashita, MD, PhD1 and Yasuhisa Shinomura, MD, PhD1 doi:10.1038/ajg.2014.227
To the Editor: Cap polyposis is a rare disease characterized by mucoid, bloody diarrhea, and polyps covered by a cap of fibrinopurulent mucous. Neither optimal treatment nor the etiology has been established. Polyp removal appears to provide only temporary relief (1), although cure is possible in patients with solitary lesions (2). We herein describe a patient with extensive cap polyposis whose disorganized tight junctions led to the manifestation of protein-losing enteropathy. The patient’s condition was successfully eradicated by polypectomy. A 43-year-old man was referred to our university hospital because of intractable bloody diarrhea and hypoproteinemia. Upon admission, he was seen to have been experiencing 12 bowel movements a day with straining, and exhibited moderate pitting edema extending up to both knees. Blood tests revealed a total protein level of 5.1 g/dl, an albumin level of 2.2 g/dl, and severe anemia with a hemoglobin concentration of 8.7 g/dl. Approximately 500 polyps involving the entire colon, excluding the cecum and ascending colon (Figure 1a), were removed by seven polypectomy procedures (Figure 1b). The total protein, albumin, and hemoglobin levels recovered to the reference ranges, and the diarrhea disappeared. No signs of polyp recurrence were present 1 year after the first visit (6 months after the last polypectomy). The two novel findings in this case are that polypectomy with curative intent can be safe and minimally invasive and that the polyps in patients with cap polyposis can be “leaky.” The American Journal of GASTROENTEROLOGY
1689
1690
Letters to the Editor
nature publishing group
Figure 1. Colonoscopic images and immunofluorescent analysis. (a) Initial colonoscopic image at the hepatic flexure, in which the polyps were most densely located. (b) Last colonoscopic image after seven polypectomy procedures at the same portion of the panel a.
Figure 2. Immunofluorescence analysis of tight junctions. Claudin-2 in the polyp epithelia (a) and normal colonic epithelia (b) in the present case. Claudin-7 in the polyp epithelia (c) and normal colonic epithelia (d) in the present case. The slides are viewed under a confocal microscope (LSM 510 META ConfoCor 3; Carl Zeiss, Oberkochen, Germany). Excitation at 543 nm induced Alexa Fluor 488 fluorescence (green emission) for claudin-2 and -7, whereas excitation at 364 nm induced 4,6-diamidino-2-phenylindole fluorescence of nuclei (blue emission).
Our patient underwent multiple polypectomy procedures with no serious complications or signs of recurrence throughout The American Journal of GASTROENTEROLOGY
a 1-year observation period. These findings suggest that the currently established recommendations are based on anecdo-
tal evidence: polypectomy is indicated for fewer than 10 polyps (1,2), whereas surgical resection is required for greater numbers of polyps. In addition, there is reportedly a potentially increased risk for postpolypectomy bleeding in such cases. As polyposis can recur even after proctocolectomy (3), semitotal colectomy, which would be inevitable to treat our patient, is not always curable. Such devastating surgery seems unrealistic, but minimally invasive polypectomy seems preferable for the benign nature of the disease. We also found that the polyps in cap polyposis can be “leaky.” We believe that, when cap polyposis manifests as protein-losing enteropathy, serum proteins are exclusively lost from the fibrinopurulent cap at the tip of the polyps because of the absence of epithelial barriers. Surprisingly, the barrier integrity of the polyps in our patients was broadly impaired even in the intact, covered epithelia, in which pore-forming claudin-2 was abnormally upregulated and redistributed (Figure 2a and b) (4). Conversely, the levels of pore-sealing claudin-7 were downregulated in our patient (Figure 2c and d). In the large intestine, claudin-2 is only detected in the deep crypts by expression in gradients along the crypt-to-villous axis (5), whereas claudin-7 is expressed more strongly on basolateral surfaces of the intestinal epithelium than on the apical tips (6). Tight junctions are the most apical junctional complex backboned by claudins. The perturbation of claudins compellingly suggests that extensive polypectomy is an effective and preferable treatment option for cap polyposis. In conclusion, we have described a patient with extensive cap polyposis that manifested as protein-losing enteropathy, which was successfully treated by definitive polypectomy. Establishment of optimal management protocols for gastrointestinal polyposis syndromes such as cap polyposis is urgently needed. ACKNOWLEDGMENTS We are very grateful to E. Katahira at the Department of Gastroenterology, Rheumatology, and Clinical Immunology, for providing technical assistance. CONFLICT OF INTEREST Guarantor of the article: Yoshiaki Arimura, MD, PhD. VOLUME 109 | OCTOBER 2014 www.amjgastro.com
Letters to the Editor
nature publishing group
Specific author contributions: All authors had access to the data, had a role in the writing of the manuscript, and approved the final version for submission. Financial support: None. Potential competing interests: None. REFERENCES 1. Akamatsu T, Nakamura N, Kawamura Y et al. Possible relationship between Helicobacter pylori infection and cap polyposis of the colon. Helicobacter 2004;9:651–6.
© 2014 by the American College of Gastroenterology
2. Ng K-H, Mathur P, Kumarasinghe MP et al. Cap polyposis: further experience and review. Dis Colon Rectum 2004;47:1208–15. 3. Konishi T, Watanabe T, Takei Y et al. Confined progression of cap polyposis along the anastomotic line, implicating the role of inflammatory responses in the pathogenesis. Gastrointest Endosc 2005;62:446–7. 4. Furuse M, Furuse K, Sasaki H et al. Conversion of zonulae occludentes from tight to leaky strand type by introducing claudin-2 into Madin-Darby canine kidney I cells. J Cell Biol 2001;153:263–72. 5. Chiba H, Osanai M, Murata M et al. Transmembrane proteins of tight junctions. Biochim Biophys Acta 2008;1778:588–600.
6. Fujita H, Chiba H, Yokozaki H et al. Differential expression and subcellular localization of claudin-7, -8, -12, -13, and -15 along the mouse intestine. J Histochem Cytochem 2006;54: 933–44. 1
Department of Gastroenterology, Rheumatology, and Clinical Immunology, Sapporo Medical University, Sapporo, Japan. Correspondence: Yoshiaki Arimura, MD, PhD, Department of Gastroenterology, Rheumatology, and Clinical Immunology, Sapporo Medical University, S-1, W-16, Chuo-ku, Sapporo 060-8543, Japan. E-mail: [email protected]
The American Journal of GASTROENTEROLOGY
1691
