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Brain-gut interactions in ulcerative colitis
GASTROENTEROLOGY 2000;118:807–809
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.
Which Is the Hen and Which Is the Egg? Dear Sir: We read with great interest the recent report by Gerlach et al.1 that further confirms an inverse relationship between viral replication and hepatitis C virus (HCV)-specific response of peripheral blood CD4⫹ T cells in HCV infection. Of particular interest is the observation that in 6 patients, strong T-cell responses were present during a transient phase of apparently low-level replication, and loss of CD4 responses was associated with reappearance of HCV RNA in the peripheral blood. Based on these observations, the authors prompt the intriguing hypothesis that a strong CD4⫹/Th1⫹ cell response has to be maintained to control HCV infection. We would like to draw attention to two observations that suggest an alternative interpretation of the relationship between HCV replication and the CD4⫹ immune response. Zitron et al.2 showed recently that the proliferative response of peripheral blood CD4⫹ T cells recovered only several weeks after loss of HCV viremia in responders
to interferon/ribavirin combination therapy. Similar to this observation, we found a hemophiliac patient from our department who had spontaneously recovered from genotype 1 HCV infection in 1982 and was HCV RNA negative thereafter.3 In line with Gerlach et al., this patient had a strong HCV-specific CD4⫹ response, which, however, was lost transiently when the patient was reinfected accidentally with a different genotype 1b isolate. The patient had pronounced symptomatic hepatitis with a peak alanine aminotransferase (ALT) level of 505 U/L, and his reinfection cleared despite the apparent absence of any proliferative T-cell responses (Figure 1). Six months after elimination of HCV, the patient’s proliferative responses had recovered to the same level as before reinfection. These two additional observations offer another explanation: that it is the HCV replication that affects the T-cell response in the peripheral blood rather than the loss of CD4-mediated immune control that causes reappearance of HCV viremia. It might be interesting for the authors to analyze their data in light of this alternative putative explanation. UTA DU¨ESBERG TILMAN SAUERBRUCH ULRICH SPENGLER Department of Internal Medicine I University of Bonn Bonn, Germany 1. Gerlach JT, Diepolder HM, Jung MC, et al. Recurrence of hepatitis C after loss of virus-specific CD4⫹ T-cell response in acute hepatitis C. Gastroenterology 1999;117:933–941. 2. Zitron IM, Qu S, Sridhar N, et al. Immune responses to hepatitis C virus proteins by PBMCs from patients responding to treatment with interferon ⫹ ribavirin (abstr). Hepatology 1999;30(suppl 1): 452A. 3. Du¨esberg U, Kaiser R, Brackmann H, et al. Viral clearance associated with transient loss of peripheral blood T cell reactivity in a patient with HCV reinfection—a case report (submitted). doi:10.1053/gg.2000.6761
Brain-Gut Interactions in Ulcerative Colitis
Figure 1. Immune response and viral parameters during HCV reinfection. HCV-RNA results: ⫺, Negative PCR result; ⫹, positive PCR result. Serum ALT levels (international units) were measured by routine biochemistry. T-cell proliferation (4-hour tritium-thymidine uptake) in response to recombinant HCV core, NS3, NS4, and NS5 proteins was measured in Ficoll-separated peripheral blood mononuclear cells. Results are shown as stimulation indices (SI) relative to the buffer control.
Dear Sir: The case report of Kemler et al.1 described a convincing association of spinal cord simulation and relapses of ulcerative colitis in a 48-year-old man who was receiving treatment for posttraumatic pain related to an earlier fracture of his right arm. Correspondence from Barbara et al.2 suggested that the colitic relapses in Kemler’s patient reflected neurogenic inflammation that involved the release of substance P from spinal sensory afferents within the colon. Our experience leads us to agree with the view of Barbara et al. and to suggest further that stimulation of the spinal cord at the level of C4–C8 activated a descending pathway from the brain to the large bowel in the patient described by Kemler et al. We reviewed the records of 4000 spinal cord–injured patients, who were quadriplegic or paraplegic, to test the hypothesis that transection of the spinal cord above T4 would prevent or alter the course of
808 CORRESPONDENCE
ulcerative colitis. The records examined included the Mayo Clinic in Rochester, Minnesota, and the Veterans Administration Spinal Cord Injury Services in Palo Alto and Long Beach, California. No cases of ulcerative colitis were found in any of the records for patients with complete spinal transaction above T4. Nevertheless, based on the incidence and prevalence data for ulcerative colitis in the Rochester, Minnesota, community population,3 our results for the 4K spinal cord patients did not reach statistical significance. We were reminded of a patient in our study population who was diagnosed with ulcerative colitis at age 40 and at age 56 underwent a partial colonic resection to remove adenocarcinoma. After surgery, he had multiple relapses of colitis. When the patient was 62 years, a fall from a ladder resulted in Brown–Se´quard’s paralysis at the C5 level. Complete remission of his colitis followed the spinal injury, and periodic checkups over a 5-year period found no evidence of colitis. Evidence from our studies on the cotton-top tamarin, nonhuman primate model for ulcerative colitis and colon cancer, also supports the hypothesis of a brain-gut connection in colitis. Environmental stress is clearly a factor in the initiation and progression of colitis in the tamarin model.4–6 Consistent with the suggestion of Barbara et al.2 for involvement of substance P, we found that twice-daily oral dosing with a nonpeptide neurokinin-1 antagonist suppressed the acute inflammatory response in the colon of cotton-top tamarins when the monkeys were removed from their natural habitat to a colitis-inducing environment.7 Our overall working hypothesis is for a brain–mast cell connection that, during physical or emotional stress, degranulates enteric mast cells to release simultaneously both chemical signals to the enteric nervous system and chemoattractant factors for inflammatory cells. Actions of mast cell mediators in the enteric nervous system underlie symptoms of diarrhea and lower abdominal discomfort; chemoattractant actions at the intestinal vasculature initiate the inflammatory cascade.8,9 OWEN C. PECK, M.D. School of Medicine University of Nevada Reno, Nevada JACKIE D. WOOD, Ph.D. Department of Physiology and Internal Medicine College of Medicine and Public Health Ohio State University Columbus, Ohio 1. Kemler MA, Barendse GAM, Van Kleef M. Relapsing ulcerative colitis associated with spinal cord stimulation. Gastroenterology 1999;117:215–217. 2. Barbara G, De Giorgio R, Stanghellini V, et al. Relapsing ulcerative colitis after spinal cord stimulation: a case of intestinal neurogenic inflammation? (letter) Gastroenterology 1999;117:1256–1257. 3. Stonnington CM, Phillips SF, Meltion LJ, et al. Chronic ulcerative colitis: incidence and prevalence in a community. Gut 1987;28:402– 409. 4. Stonerook MJ, Weiss HS, Rodriguez-M, et al. Temperaturemetabolism relations in the cotton-top tamarin (Saguinus oedipus) model for ulcerative colitis. J Med Primatol 1994;23:16–22. 5. Wood JD, Peck OC, Tefend KS, et al. Colitis and colon cancer in cotton-top tamarins (Saguinus oedipus oedipus) living wild in their natural habitat. Dig Dis Sci 1998;43:1443–1453. 6. Wood JD, Peck OC, Tefend KS, et al. Evidence that colitis is initiated by environmental stress and sustained by fecal factors in
GASTROENTEROLOGY Vol. 118, No. 4
the cotton-top tamarin (Saguinus oedipus). Dig Dis Sci 2000 (in press). 7. Wood JD, Peck OC, Sharma HS, et al. A non-peptide neurokinin 1 (NK-1) receptor antagonist suppresses initiation of acute inflammation in the colon of the cotton-top tamarin model for spontaneous colitis and colon cancer (abstr). Gastroenterology 1996;110: A1047. 8. Wood JD. Enteric neuro-pathobiology. In: Phillips SF, Wingate D, eds. Functional disorders of the gut: a handbook for clinicians. London: Harcourt Brace, 1998:19–42. 9. Wood JD, Alpers DH, Andrews PLR. Fundamentals of neurogastroenterology. Gut 1999;45:1–44. doi:10.1053/gg.2000.6762
When Should Endoscopic Screening in Familial Adenomatous Polyposis Be Started? Dear Sir: Familial adenomatous polyposis (FAP) is an autosomal dominant disease characterized by development of hundreds of polyps in the colorectum early in life. If patients are left untreated, virtually all develop colorectal cancer. Studies on the natural history of the disease show that patients develop polyps in the second and third decade of life. Although all investigators agree to start screening of the rectum at adolescence, there is no consensus on the proper age at which screening should start. We performed a survey among members of the Dutch Polyposis Patients Association. Because sigmoidoscopy is a burdensome procedure especially when performed early in life, the decision should be made carefully. Approximately 1% of the polyposis patients will develop colorectal cancer between ages 15 and 20 years. Most investigators recommend to start screening before age 15, because they consider that a 1% cancer risk is unacceptable for the patients. Most specialists even recommend to start at age 12 based on experience that sigmoidoscopy is better accepted before puberty. To inventory the opinion of the patients, we conducted a survey among members of the Dutch Polyposis Patients Association. The questionnaire addressed the following questions: (1) How did the patients experience their first endoscopy? (2) At what age should screening start given the 1% cancer risk between ages 15 and 20 years? (3) Do the patients believe that endoscopy is better accepted before puberty? (4) At what age should screening be started in their children, and (5) at what age should genetic screening (DNA testing) be performed in their children? Ninety-nine (56%) patients, 50 male and 49 female, returned a completed questionnaire. Forty-one percent of the respondents underTable 1. At Which Age Should Screening Commence in the Children of Patients With FAP? Age ( yr )
No. of respondents (% )
10–12 12–15 15–20
50 (51) 22 (22) 20 (20)
NOTE. The survey showed that most FAP patients agree with the recommendation to start screening between ages 10 and 12. However, a significant proportion would like to start the examinations in their children at a more advanced age. We suggest to follow an individual approach and to discuss the argument relevant for the decision making with the patients and parents.
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.
Which Is the Hen and Which Is the Egg? Dear Sir: We read with great interest the recent report by Gerlach et al.1 that further confirms an inverse relationship between viral replication and hepatitis C virus (HCV)-specific response of peripheral blood CD4⫹ T cells in HCV infection. Of particular interest is the observation that in 6 patients, strong T-cell responses were present during a transient phase of apparently low-level replication, and loss of CD4 responses was associated with reappearance of HCV RNA in the peripheral blood. Based on these observations, the authors prompt the intriguing hypothesis that a strong CD4⫹/Th1⫹ cell response has to be maintained to control HCV infection. We would like to draw attention to two observations that suggest an alternative interpretation of the relationship between HCV replication and the CD4⫹ immune response. Zitron et al.2 showed recently that the proliferative response of peripheral blood CD4⫹ T cells recovered only several weeks after loss of HCV viremia in responders
to interferon/ribavirin combination therapy. Similar to this observation, we found a hemophiliac patient from our department who had spontaneously recovered from genotype 1 HCV infection in 1982 and was HCV RNA negative thereafter.3 In line with Gerlach et al., this patient had a strong HCV-specific CD4⫹ response, which, however, was lost transiently when the patient was reinfected accidentally with a different genotype 1b isolate. The patient had pronounced symptomatic hepatitis with a peak alanine aminotransferase (ALT) level of 505 U/L, and his reinfection cleared despite the apparent absence of any proliferative T-cell responses (Figure 1). Six months after elimination of HCV, the patient’s proliferative responses had recovered to the same level as before reinfection. These two additional observations offer another explanation: that it is the HCV replication that affects the T-cell response in the peripheral blood rather than the loss of CD4-mediated immune control that causes reappearance of HCV viremia. It might be interesting for the authors to analyze their data in light of this alternative putative explanation. UTA DU¨ESBERG TILMAN SAUERBRUCH ULRICH SPENGLER Department of Internal Medicine I University of Bonn Bonn, Germany 1. Gerlach JT, Diepolder HM, Jung MC, et al. Recurrence of hepatitis C after loss of virus-specific CD4⫹ T-cell response in acute hepatitis C. Gastroenterology 1999;117:933–941. 2. Zitron IM, Qu S, Sridhar N, et al. Immune responses to hepatitis C virus proteins by PBMCs from patients responding to treatment with interferon ⫹ ribavirin (abstr). Hepatology 1999;30(suppl 1): 452A. 3. Du¨esberg U, Kaiser R, Brackmann H, et al. Viral clearance associated with transient loss of peripheral blood T cell reactivity in a patient with HCV reinfection—a case report (submitted). doi:10.1053/gg.2000.6761
Brain-Gut Interactions in Ulcerative Colitis
Figure 1. Immune response and viral parameters during HCV reinfection. HCV-RNA results: ⫺, Negative PCR result; ⫹, positive PCR result. Serum ALT levels (international units) were measured by routine biochemistry. T-cell proliferation (4-hour tritium-thymidine uptake) in response to recombinant HCV core, NS3, NS4, and NS5 proteins was measured in Ficoll-separated peripheral blood mononuclear cells. Results are shown as stimulation indices (SI) relative to the buffer control.
Dear Sir: The case report of Kemler et al.1 described a convincing association of spinal cord simulation and relapses of ulcerative colitis in a 48-year-old man who was receiving treatment for posttraumatic pain related to an earlier fracture of his right arm. Correspondence from Barbara et al.2 suggested that the colitic relapses in Kemler’s patient reflected neurogenic inflammation that involved the release of substance P from spinal sensory afferents within the colon. Our experience leads us to agree with the view of Barbara et al. and to suggest further that stimulation of the spinal cord at the level of C4–C8 activated a descending pathway from the brain to the large bowel in the patient described by Kemler et al. We reviewed the records of 4000 spinal cord–injured patients, who were quadriplegic or paraplegic, to test the hypothesis that transection of the spinal cord above T4 would prevent or alter the course of
808 CORRESPONDENCE
ulcerative colitis. The records examined included the Mayo Clinic in Rochester, Minnesota, and the Veterans Administration Spinal Cord Injury Services in Palo Alto and Long Beach, California. No cases of ulcerative colitis were found in any of the records for patients with complete spinal transaction above T4. Nevertheless, based on the incidence and prevalence data for ulcerative colitis in the Rochester, Minnesota, community population,3 our results for the 4K spinal cord patients did not reach statistical significance. We were reminded of a patient in our study population who was diagnosed with ulcerative colitis at age 40 and at age 56 underwent a partial colonic resection to remove adenocarcinoma. After surgery, he had multiple relapses of colitis. When the patient was 62 years, a fall from a ladder resulted in Brown–Se´quard’s paralysis at the C5 level. Complete remission of his colitis followed the spinal injury, and periodic checkups over a 5-year period found no evidence of colitis. Evidence from our studies on the cotton-top tamarin, nonhuman primate model for ulcerative colitis and colon cancer, also supports the hypothesis of a brain-gut connection in colitis. Environmental stress is clearly a factor in the initiation and progression of colitis in the tamarin model.4–6 Consistent with the suggestion of Barbara et al.2 for involvement of substance P, we found that twice-daily oral dosing with a nonpeptide neurokinin-1 antagonist suppressed the acute inflammatory response in the colon of cotton-top tamarins when the monkeys were removed from their natural habitat to a colitis-inducing environment.7 Our overall working hypothesis is for a brain–mast cell connection that, during physical or emotional stress, degranulates enteric mast cells to release simultaneously both chemical signals to the enteric nervous system and chemoattractant factors for inflammatory cells. Actions of mast cell mediators in the enteric nervous system underlie symptoms of diarrhea and lower abdominal discomfort; chemoattractant actions at the intestinal vasculature initiate the inflammatory cascade.8,9 OWEN C. PECK, M.D. School of Medicine University of Nevada Reno, Nevada JACKIE D. WOOD, Ph.D. Department of Physiology and Internal Medicine College of Medicine and Public Health Ohio State University Columbus, Ohio 1. Kemler MA, Barendse GAM, Van Kleef M. Relapsing ulcerative colitis associated with spinal cord stimulation. Gastroenterology 1999;117:215–217. 2. Barbara G, De Giorgio R, Stanghellini V, et al. Relapsing ulcerative colitis after spinal cord stimulation: a case of intestinal neurogenic inflammation? (letter) Gastroenterology 1999;117:1256–1257. 3. Stonnington CM, Phillips SF, Meltion LJ, et al. Chronic ulcerative colitis: incidence and prevalence in a community. Gut 1987;28:402– 409. 4. Stonerook MJ, Weiss HS, Rodriguez-M, et al. Temperaturemetabolism relations in the cotton-top tamarin (Saguinus oedipus) model for ulcerative colitis. J Med Primatol 1994;23:16–22. 5. Wood JD, Peck OC, Tefend KS, et al. Colitis and colon cancer in cotton-top tamarins (Saguinus oedipus oedipus) living wild in their natural habitat. Dig Dis Sci 1998;43:1443–1453. 6. Wood JD, Peck OC, Tefend KS, et al. Evidence that colitis is initiated by environmental stress and sustained by fecal factors in
GASTROENTEROLOGY Vol. 118, No. 4
the cotton-top tamarin (Saguinus oedipus). Dig Dis Sci 2000 (in press). 7. Wood JD, Peck OC, Sharma HS, et al. A non-peptide neurokinin 1 (NK-1) receptor antagonist suppresses initiation of acute inflammation in the colon of the cotton-top tamarin model for spontaneous colitis and colon cancer (abstr). Gastroenterology 1996;110: A1047. 8. Wood JD. Enteric neuro-pathobiology. In: Phillips SF, Wingate D, eds. Functional disorders of the gut: a handbook for clinicians. London: Harcourt Brace, 1998:19–42. 9. Wood JD, Alpers DH, Andrews PLR. Fundamentals of neurogastroenterology. Gut 1999;45:1–44. doi:10.1053/gg.2000.6762
When Should Endoscopic Screening in Familial Adenomatous Polyposis Be Started? Dear Sir: Familial adenomatous polyposis (FAP) is an autosomal dominant disease characterized by development of hundreds of polyps in the colorectum early in life. If patients are left untreated, virtually all develop colorectal cancer. Studies on the natural history of the disease show that patients develop polyps in the second and third decade of life. Although all investigators agree to start screening of the rectum at adolescence, there is no consensus on the proper age at which screening should start. We performed a survey among members of the Dutch Polyposis Patients Association. Because sigmoidoscopy is a burdensome procedure especially when performed early in life, the decision should be made carefully. Approximately 1% of the polyposis patients will develop colorectal cancer between ages 15 and 20 years. Most investigators recommend to start screening before age 15, because they consider that a 1% cancer risk is unacceptable for the patients. Most specialists even recommend to start at age 12 based on experience that sigmoidoscopy is better accepted before puberty. To inventory the opinion of the patients, we conducted a survey among members of the Dutch Polyposis Patients Association. The questionnaire addressed the following questions: (1) How did the patients experience their first endoscopy? (2) At what age should screening start given the 1% cancer risk between ages 15 and 20 years? (3) Do the patients believe that endoscopy is better accepted before puberty? (4) At what age should screening be started in their children, and (5) at what age should genetic screening (DNA testing) be performed in their children? Ninety-nine (56%) patients, 50 male and 49 female, returned a completed questionnaire. Forty-one percent of the respondents underTable 1. At Which Age Should Screening Commence in the Children of Patients With FAP? Age ( yr )
No. of respondents (% )
10–12 12–15 15–20
50 (51) 22 (22) 20 (20)
NOTE. The survey showed that most FAP patients agree with the recommendation to start screening between ages 10 and 12. However, a significant proportion would like to start the examinations in their children at a more advanced age. We suggest to follow an individual approach and to discuss the argument relevant for the decision making with the patients and parents.