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Need for screening colonoscopy in first-degree relatives
GASTROENTEROLOGY 1997;112:2161–2164
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.
IBD-Associated Bone Loss: Is Inflammation the Explanation?
ing the role of cytokines and the effect of intervention in colitisinduced bone loss are needed.
Dear Sir: We read with interest the article by Lin et al. in the November issue of GASTROENTEROLOGY,1 which showed that experimental colitis causes bone loss in rats. The investigators reported a 33% bone loss caused by suppressed bone formation, assessed by means of bone histomorphometry of the tibia, within 3 weeks after colitis induction, followed by normalization of bone histology 12 weeks later when colitis had subsided. Their data complement and confirm our findings2; in the same model of experimental colitis, we reported that, at 3 weeks, colitis led to a reduced bone density, bone ash weight, and bone calcium content. These alterations were associated to longlasting hypercalciuria that developed within 3 days after colitis induction. However, additional losses of calcium with the feces cannot be excluded. Like Lin et al. in their first setting, we showed an increase of bone resorption as reflected by significantly elevated urinary hydroxyprolin levels at 3 weeks. Because Lin et al. excluded estrogen deficiency or hypercorticism in their experiments, the possibility that inflammatory cytokines, generated in the inflamed intestine, act on bone cells remains an attractive hypothesis. In fact, continuous infusion of interleukin 1b by osmotic minipumps decreased circulating osteocalcin by 20%–30%, reduced mineral apposition rate by 50%, and induced persistent hypercalciuria with normal serum calcium levels in the rat.3 These findings were explained as being caused by interleukin 1b, which acts as uncoupler of the bone formation-resorption linkage in vivo. WALTER FRIES, M.D. ALESSANDRO MARTIN, M.D.
Cattedra Malattie Apparato Digerente Universita` di Padova Padova, Italy 1. Lin C-L, Moniz C, Chambers TJ, Chow JWM. Colitis causes bone loss in rats through suppression of bone formation. Gastroenterology 1996;111:1263–1271. 2. Fries W, Giacomin D, Plebani M, Martin A. Effect of experimental colitis on bone metabolism in the rat. Digestion 1994;55:229– 233. 3. Ngyuen L, Dewhirst FE, Hauschka PV, Stashenko P. Interleukin1b stimulates bone resorption and inhibits bone formation in vivo. Lymphokine Cytokine Res 1991;10:15–21.
Reply. We thank Drs. Fries and Martin for their comments. The main finding of bone loss associated with colitis in both studies is clear. Our aim was to examine the mechanisms of the bone loss, at tissue level, using histomorphometric analysis of the cancellous bone. We found that suppression of bone formation was the main factor responsible for the cancellous bone loss. Increase in bone resorption was minor, by bone histomorphometric assessment. Differences in the contribution of bone resorption to the bone loss may be caused by methodological differences. Alternatively, bone resorption may occur in the cortex, which was not examined in our study. Further studies on the mechanism of bone loss, includ-
/ 5e1d$$0036
05-13-97 11:07:33
gasa
JADE CHOW
Department of Histopathology St. George’s Hospital Medical School London, England
Need for Screening Colonoscopy in First-Degree Relatives Dear Sir: I read the article by Bazzoli et al. on the risk of adenomatous polyps in asymptomatic first-degree relatives of persons with colon cancer in the September 1995 issue of GASTROENTEROLOGY1 with great interest. However, I call to your attention the fact that this question has been addressed by several studies including our own published in Diseases of the Colon and Rectum in 1992.2 In our study, 92% of first-degree relatives of patients with colorectal cancer had only 1 first-degree relative afflicted. We similarly showed back in 1992, as Bazzoli did in 1995, that compared with subjects without family histories, asymptomatic patients with 1 firstdegree relative with colorectal cancer have almost double the risk of developing adenomatous polyps. As confirmed by Bazzoli, we showed in 1992 that first-degree relative status, age, and male sex were independent risk factors for the development of colorectal adenomas. In fact, we showed that first-degree relative status had a 3.49 (confidence interval, 1.3–9.12) relative risk, higher than the 1.9 (Ç1.3– 1.8) reported by Bazzoli et al. We documented, for the first time, an increased prevalence of colonoscopically detectable adenomas in asymptomatic first-degree relatives of patients with colon cancer compared with asymptomatic controls, thus supporting the use of colonoscopy as a routine screening tool in this high-risk group of patients. I was surprised that Bazzoli et al. did not cite our work because their findings are consistent with our observation published 3 years before theirs. JOSE´ G. GUILLEM, M.D., M.P.H.
Memorial Sloan Kettering Cancer Center and Cornell University Medical College New York, New York 1. Bazzoli F, Fossi S, Scottili S, Pozzato P, Zagari RM, Morelli MC, Taroni F, Roda E. The risk of adenomatous polyps in asymptomatic first-degree relatives of persons with colon cancer. Gastroenterology 1995;109:783–788. 2. Guillem JG, Forde KA, Treat MR, Neugut AI, O’Toole KM, Diamond BE. Colonoscopic screening for neoplasms in asymtomatic firstdegree relatives of colon cancer patients: a controlled prospective study. Dis Colon Rectum 1992;35:523–529.
Reply. We thank Dr. Guillem for drawing our attention to his interesting paper published in 1992.1 In that same year, the preliminary results of our study were presented at the 93rd annual meeting of the American Gastroenterological Association.2 The completed study was published as a full paper in 1995.3
WBS-Gastro
2162 CORRESPONDENCE
GASTROENTEROLOGY Vol. 112, No. 6
Our results are consistent with the observations of Guillem et al.; we found a relative risk of 1.9 with a confidence interval from 1.3 to 2.8, whereas Dr. Guillem found a 3.49 relative risk with a wider confidence interval (1.3–9.12), probably due to the smaller size of their series and the fact that they included in their multivariate analysis patients with a more complex family history. In our study, consecutive patients were classified on the basis of colonoscopic findings (i.e., either negative colonoscopy or at least one adenomatous polyp ú5 mm in diameter), and subsequently of the family history (either positive family history, defined as the presence of only 1 first-degree relative with colon cancer, or a family history completely negative for any type of cancer). In contrast, the study of Guillem et al. was focused on the selection of subjects on the basis of a positive family history for colon cancer; such a design is probably more prone to a detection bias. Confirming the observations of Dr. Guillem, we found also a significantly higher frequency of a proximal polyp location and a greater frequency of severely dysplastic lesions. Recently presented preliminary data of a 3-year follow-up study4 indicate that the presence of a positive family history determines a significant increase in the incidence rate of new adenomatous polyps. We think that guidelines for screening programs for colorectal cancer should include total colonoscopy in asymptomatic subjects with 1 first-degree relative with colon cancer and that such a strategy could help to reduce the incidence and the mortality rates of this neoplasm. FRANCO BAZZOLI, M.D.
Dipartimento di Medicina Interna e Gastroenterologia Universita` di Bologna Policlinico S. Orsola Bologna, Italy 1. Guillem JG, Forde KA, Treat MR, Neugut AI, O’Toole KM, Diamond BE. Colonoscopic screening for neoplasms in asymptomatic firstdegree relatives of colon cancer patients. Dis Colon Rectum 1992; 35:523–529. 2. Bazzoli F, Morelli MC, Fossi S, Taroni F, Pozzato P, Zagari RM, Novelli V, Parini P, Festi D, Mazzella G, Aldini R, Roda E. Increased familial tendency for adenomatous polyps in first degree relatives of colon cancer patients and need of total colonoscopy as the initial screening tool. A case control study (abstr). Gastroenterology 1992;102:A345. 3. Bazzoli F, Fossi S, Sottili S, Pozzato P, Zagari RM, Morelli MC, Taroni F, Roda E. The risk of adenomatous polyps in asymptomatic first-degree relatives of persons with colon cancer. Gastroenterology 1995;109:783–788. 4. Bazzoli F, Fossi S, Zagari RM, Sottili S, Pozzato P, Mwangemi C, Ricciardiello L, Roda E. Incidence and recurrence rates of colorectal adenomas in first-degree relatives of colon cancer patients (abstr). Gastroenterology 1996;110:A490.
Hyperammonemia After Heart-Lung Transplantation Dear Sir: Recently Lichtenstein et al.1 reported the fatal development of unexplained hyperammonemia after lung transplantation for primary pulmonary hypertension in the absence of preexisting liver disease. We have previously described a 44-year-old white woman with both primary pulmonary hypertension (PHT) and primary biliary cirrhosis (PBC) in the absence of portal hypertension.2 At the time of writing, our patient was still awaiting a combined heart-lung transplant. We were extremely interested in the case
/ 5e1d$$0036
05-13-97 11:07:33
gasa
report of Lichtenstein because it described hyperammonemia culminating in fatal uncal herniation secondary to cerebral edema, circumstances similar to the posttransplant course of our patient whose death was perplexing because the hyperammonemia was out of keeping with the degree of liver disease. The pretransplant documentation of PHT and PBC and the lack of portal hypertension in our patient were according to previously reported findings.2 Two years after the diagnosis of PHT and PBC, our patient underwent heart-lung transplantation. Immunosuppression consisted of OKT3, azathioprine, and corticosteroids with cyclosporine introduced on the 13th posttransplant day. Nutrition was instituted with enteral feeds. Initially there was a transient coagulopathy that rapidly corrected and was attributed to intraoperative aprotinin administration (the INR immediately preoperatively was 1.25). Renal failure, hypotension requiring inotropic agents, and pneumonia in the donor lungs (Staphylococcus aureus and Pseudomonas spp) with acute respiratory distress syndrome developed soon afterwards. On the 15th posttransplant day, after the patient’s level of consciousness failed to improve after reversal of neuromuscular blockade and withdrawal of sedation, arterial ammonia level was found to be markedly elevated at 428 mmol/L (õ35 mmol/L). The liver enzymes at the time were as follows: total bilirubin, 92 mmol/L (5.4 mg/dL); alkaline phosphatase, 383 U/L; alanine aminotransferase, 28 U/L; and aspartate aminotransferase, 54 U/L. The patient’s multisystem organ failure did not improve, and she became comatose. A computerized tomographic scan of her head revealed cerebral edema with bilateral uncal herniation and intracerbral hemorrhage; medical treatment was withdrawn. In the postmortem, autopsy showed absolutely no evidence of portal hypertension, and gross examination of the liver showed it to be soft, slightly nodular, but not cirrhotic. Histological examination of the liver showed only portal tract changes consistent with PBC. Until Lichtenstein et al. reported their case, we were unaware of any similar experiences reported after lung-cardiac transplantation and felt that our experience was both unusual and isolated. Lichtenstein et al. were not able to explain the hyperammonemia in their patient, and neither were we. We speculated that the hyperammonemia in our case was an unexplained metabolic manifestation of multisystem organ failure in a patient perhaps predisposed by coincident, albeit mild, liver disease. Our experience and the report of Lichtenstein (as well as the unpublished anecdotal cases that were mentioned in the article) suggest that hyperammonemia may be a rare but real complication of organ transplantation. ERIC M. YOSHIDA, M.D., F.R.C.P.(C) DAVID N. OSTROW, M.D., F.R.C.P.(C) SIEGFRIED R. ERB, M.D., F.R.C.P.(C) Department of Medicine GUY FRADET, M.D., F.R.C.S.(C)
Department of Surgery University of British Columbia, Vancouver British Columbia, Canada, and the British Columbia Transplant Society 1. Lichtenstein GR, Kaiser LR, Tuchman M, Palevsky HI, Kotloff RM, O’Brien CB, et al. Fatal hyperammonemia following orthotopic lung transplantation. Gastroenterology 1997;112:236–240. 2. Yoshida EM, Erb SR, Ostrow DN, Ricci DR, Scudamore CH, Fradet G. Pulmonary hypertension associated with primary biliary cirrhosis in the absence of portal hypertension: a case report. Gut 1994; 35:280–282.
WBS-Gastro
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.
IBD-Associated Bone Loss: Is Inflammation the Explanation?
ing the role of cytokines and the effect of intervention in colitisinduced bone loss are needed.
Dear Sir: We read with interest the article by Lin et al. in the November issue of GASTROENTEROLOGY,1 which showed that experimental colitis causes bone loss in rats. The investigators reported a 33% bone loss caused by suppressed bone formation, assessed by means of bone histomorphometry of the tibia, within 3 weeks after colitis induction, followed by normalization of bone histology 12 weeks later when colitis had subsided. Their data complement and confirm our findings2; in the same model of experimental colitis, we reported that, at 3 weeks, colitis led to a reduced bone density, bone ash weight, and bone calcium content. These alterations were associated to longlasting hypercalciuria that developed within 3 days after colitis induction. However, additional losses of calcium with the feces cannot be excluded. Like Lin et al. in their first setting, we showed an increase of bone resorption as reflected by significantly elevated urinary hydroxyprolin levels at 3 weeks. Because Lin et al. excluded estrogen deficiency or hypercorticism in their experiments, the possibility that inflammatory cytokines, generated in the inflamed intestine, act on bone cells remains an attractive hypothesis. In fact, continuous infusion of interleukin 1b by osmotic minipumps decreased circulating osteocalcin by 20%–30%, reduced mineral apposition rate by 50%, and induced persistent hypercalciuria with normal serum calcium levels in the rat.3 These findings were explained as being caused by interleukin 1b, which acts as uncoupler of the bone formation-resorption linkage in vivo. WALTER FRIES, M.D. ALESSANDRO MARTIN, M.D.
Cattedra Malattie Apparato Digerente Universita` di Padova Padova, Italy 1. Lin C-L, Moniz C, Chambers TJ, Chow JWM. Colitis causes bone loss in rats through suppression of bone formation. Gastroenterology 1996;111:1263–1271. 2. Fries W, Giacomin D, Plebani M, Martin A. Effect of experimental colitis on bone metabolism in the rat. Digestion 1994;55:229– 233. 3. Ngyuen L, Dewhirst FE, Hauschka PV, Stashenko P. Interleukin1b stimulates bone resorption and inhibits bone formation in vivo. Lymphokine Cytokine Res 1991;10:15–21.
Reply. We thank Drs. Fries and Martin for their comments. The main finding of bone loss associated with colitis in both studies is clear. Our aim was to examine the mechanisms of the bone loss, at tissue level, using histomorphometric analysis of the cancellous bone. We found that suppression of bone formation was the main factor responsible for the cancellous bone loss. Increase in bone resorption was minor, by bone histomorphometric assessment. Differences in the contribution of bone resorption to the bone loss may be caused by methodological differences. Alternatively, bone resorption may occur in the cortex, which was not examined in our study. Further studies on the mechanism of bone loss, includ-
/ 5e1d$$0036
05-13-97 11:07:33
gasa
JADE CHOW
Department of Histopathology St. George’s Hospital Medical School London, England
Need for Screening Colonoscopy in First-Degree Relatives Dear Sir: I read the article by Bazzoli et al. on the risk of adenomatous polyps in asymptomatic first-degree relatives of persons with colon cancer in the September 1995 issue of GASTROENTEROLOGY1 with great interest. However, I call to your attention the fact that this question has been addressed by several studies including our own published in Diseases of the Colon and Rectum in 1992.2 In our study, 92% of first-degree relatives of patients with colorectal cancer had only 1 first-degree relative afflicted. We similarly showed back in 1992, as Bazzoli did in 1995, that compared with subjects without family histories, asymptomatic patients with 1 firstdegree relative with colorectal cancer have almost double the risk of developing adenomatous polyps. As confirmed by Bazzoli, we showed in 1992 that first-degree relative status, age, and male sex were independent risk factors for the development of colorectal adenomas. In fact, we showed that first-degree relative status had a 3.49 (confidence interval, 1.3–9.12) relative risk, higher than the 1.9 (Ç1.3– 1.8) reported by Bazzoli et al. We documented, for the first time, an increased prevalence of colonoscopically detectable adenomas in asymptomatic first-degree relatives of patients with colon cancer compared with asymptomatic controls, thus supporting the use of colonoscopy as a routine screening tool in this high-risk group of patients. I was surprised that Bazzoli et al. did not cite our work because their findings are consistent with our observation published 3 years before theirs. JOSE´ G. GUILLEM, M.D., M.P.H.
Memorial Sloan Kettering Cancer Center and Cornell University Medical College New York, New York 1. Bazzoli F, Fossi S, Scottili S, Pozzato P, Zagari RM, Morelli MC, Taroni F, Roda E. The risk of adenomatous polyps in asymptomatic first-degree relatives of persons with colon cancer. Gastroenterology 1995;109:783–788. 2. Guillem JG, Forde KA, Treat MR, Neugut AI, O’Toole KM, Diamond BE. Colonoscopic screening for neoplasms in asymtomatic firstdegree relatives of colon cancer patients: a controlled prospective study. Dis Colon Rectum 1992;35:523–529.
Reply. We thank Dr. Guillem for drawing our attention to his interesting paper published in 1992.1 In that same year, the preliminary results of our study were presented at the 93rd annual meeting of the American Gastroenterological Association.2 The completed study was published as a full paper in 1995.3
WBS-Gastro
2162 CORRESPONDENCE
GASTROENTEROLOGY Vol. 112, No. 6
Our results are consistent with the observations of Guillem et al.; we found a relative risk of 1.9 with a confidence interval from 1.3 to 2.8, whereas Dr. Guillem found a 3.49 relative risk with a wider confidence interval (1.3–9.12), probably due to the smaller size of their series and the fact that they included in their multivariate analysis patients with a more complex family history. In our study, consecutive patients were classified on the basis of colonoscopic findings (i.e., either negative colonoscopy or at least one adenomatous polyp ú5 mm in diameter), and subsequently of the family history (either positive family history, defined as the presence of only 1 first-degree relative with colon cancer, or a family history completely negative for any type of cancer). In contrast, the study of Guillem et al. was focused on the selection of subjects on the basis of a positive family history for colon cancer; such a design is probably more prone to a detection bias. Confirming the observations of Dr. Guillem, we found also a significantly higher frequency of a proximal polyp location and a greater frequency of severely dysplastic lesions. Recently presented preliminary data of a 3-year follow-up study4 indicate that the presence of a positive family history determines a significant increase in the incidence rate of new adenomatous polyps. We think that guidelines for screening programs for colorectal cancer should include total colonoscopy in asymptomatic subjects with 1 first-degree relative with colon cancer and that such a strategy could help to reduce the incidence and the mortality rates of this neoplasm. FRANCO BAZZOLI, M.D.
Dipartimento di Medicina Interna e Gastroenterologia Universita` di Bologna Policlinico S. Orsola Bologna, Italy 1. Guillem JG, Forde KA, Treat MR, Neugut AI, O’Toole KM, Diamond BE. Colonoscopic screening for neoplasms in asymptomatic firstdegree relatives of colon cancer patients. Dis Colon Rectum 1992; 35:523–529. 2. Bazzoli F, Morelli MC, Fossi S, Taroni F, Pozzato P, Zagari RM, Novelli V, Parini P, Festi D, Mazzella G, Aldini R, Roda E. Increased familial tendency for adenomatous polyps in first degree relatives of colon cancer patients and need of total colonoscopy as the initial screening tool. A case control study (abstr). Gastroenterology 1992;102:A345. 3. Bazzoli F, Fossi S, Sottili S, Pozzato P, Zagari RM, Morelli MC, Taroni F, Roda E. The risk of adenomatous polyps in asymptomatic first-degree relatives of persons with colon cancer. Gastroenterology 1995;109:783–788. 4. Bazzoli F, Fossi S, Zagari RM, Sottili S, Pozzato P, Mwangemi C, Ricciardiello L, Roda E. Incidence and recurrence rates of colorectal adenomas in first-degree relatives of colon cancer patients (abstr). Gastroenterology 1996;110:A490.
Hyperammonemia After Heart-Lung Transplantation Dear Sir: Recently Lichtenstein et al.1 reported the fatal development of unexplained hyperammonemia after lung transplantation for primary pulmonary hypertension in the absence of preexisting liver disease. We have previously described a 44-year-old white woman with both primary pulmonary hypertension (PHT) and primary biliary cirrhosis (PBC) in the absence of portal hypertension.2 At the time of writing, our patient was still awaiting a combined heart-lung transplant. We were extremely interested in the case
/ 5e1d$$0036
05-13-97 11:07:33
gasa
report of Lichtenstein because it described hyperammonemia culminating in fatal uncal herniation secondary to cerebral edema, circumstances similar to the posttransplant course of our patient whose death was perplexing because the hyperammonemia was out of keeping with the degree of liver disease. The pretransplant documentation of PHT and PBC and the lack of portal hypertension in our patient were according to previously reported findings.2 Two years after the diagnosis of PHT and PBC, our patient underwent heart-lung transplantation. Immunosuppression consisted of OKT3, azathioprine, and corticosteroids with cyclosporine introduced on the 13th posttransplant day. Nutrition was instituted with enteral feeds. Initially there was a transient coagulopathy that rapidly corrected and was attributed to intraoperative aprotinin administration (the INR immediately preoperatively was 1.25). Renal failure, hypotension requiring inotropic agents, and pneumonia in the donor lungs (Staphylococcus aureus and Pseudomonas spp) with acute respiratory distress syndrome developed soon afterwards. On the 15th posttransplant day, after the patient’s level of consciousness failed to improve after reversal of neuromuscular blockade and withdrawal of sedation, arterial ammonia level was found to be markedly elevated at 428 mmol/L (õ35 mmol/L). The liver enzymes at the time were as follows: total bilirubin, 92 mmol/L (5.4 mg/dL); alkaline phosphatase, 383 U/L; alanine aminotransferase, 28 U/L; and aspartate aminotransferase, 54 U/L. The patient’s multisystem organ failure did not improve, and she became comatose. A computerized tomographic scan of her head revealed cerebral edema with bilateral uncal herniation and intracerbral hemorrhage; medical treatment was withdrawn. In the postmortem, autopsy showed absolutely no evidence of portal hypertension, and gross examination of the liver showed it to be soft, slightly nodular, but not cirrhotic. Histological examination of the liver showed only portal tract changes consistent with PBC. Until Lichtenstein et al. reported their case, we were unaware of any similar experiences reported after lung-cardiac transplantation and felt that our experience was both unusual and isolated. Lichtenstein et al. were not able to explain the hyperammonemia in their patient, and neither were we. We speculated that the hyperammonemia in our case was an unexplained metabolic manifestation of multisystem organ failure in a patient perhaps predisposed by coincident, albeit mild, liver disease. Our experience and the report of Lichtenstein (as well as the unpublished anecdotal cases that were mentioned in the article) suggest that hyperammonemia may be a rare but real complication of organ transplantation. ERIC M. YOSHIDA, M.D., F.R.C.P.(C) DAVID N. OSTROW, M.D., F.R.C.P.(C) SIEGFRIED R. ERB, M.D., F.R.C.P.(C) Department of Medicine GUY FRADET, M.D., F.R.C.S.(C)
Department of Surgery University of British Columbia, Vancouver British Columbia, Canada, and the British Columbia Transplant Society 1. Lichtenstein GR, Kaiser LR, Tuchman M, Palevsky HI, Kotloff RM, O’Brien CB, et al. Fatal hyperammonemia following orthotopic lung transplantation. Gastroenterology 1997;112:236–240. 2. Yoshida EM, Erb SR, Ostrow DN, Ricci DR, Scudamore CH, Fradet G. Pulmonary hypertension associated with primary biliary cirrhosis in the absence of portal hypertension: a case report. Gut 1994; 35:280–282.
WBS-Gastro