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Does growth hormone and glutamine enhance bowel absorption?
GASTROENTEROLOGY 1998;114:1110–1116
CORRESPONDENCE AAPC: Are Current Screening Recommendations Enough? Dear Sir: In 1990 a large kindred with a known mutation of the attenuated adenomatous polyposis coli (AAPC) gene and varied phenotypic expression was described.1 Frequent surveillance for members carrying the mutation has been recommended. In August 1997 a case report described malignant transformation of a fundic gland polyp in 1 of the family members. Previously, it was considered that fundic gland polyps had little or no chance of developing malignancy. As a result of this case report, it was recommended that fundic gland polyps be biopsied as an adjunct to prior screening recommendations.2 Over the last 5 years, the brother of the patient described in the case report has been followed up at our facility. He has undergone surveillance every 1–2 years via esophagogastroduodenoscopy, colonoscopy, and appropriate biopsies. His most recent study in August of 1997 revealed several small mammilations throughout the colon (but no larger polyps or cancer) and a sheet of hyperplastic polyps in the gastric fundus. Biopsies of the fundic gland polyps and gastric antrum proved unrevealing. A barium swallow and small bowel followthrough in 1994 showed no sign of polyps in the small bowel. In September 1997, the patient presented with right upper quadrant abdominal pain, generalized fatigue, and early satiety. Chemistries showed elevated alkaline phosphatase and aspartine transferase levels. Computed topography of the abdomen showed multiple densities in the liver suggestive of malignancy. Needle biopsy confirmed the diagnosis of moderately differentiated adenocarcinoma. With no evidence of primary lesion, endoscopic ultrasound examination of the gastric fundus was performed. It proved unremarkable. The implication that a second family member in this kindred may have developed a malignancy with no discernible source despite careful screening suggests that current screening recommendations may not be sufficient. Further study of other modalities would seem warranted to prevent similar unexpected metastases. JOHN LOBITZ, M.D. MICAH THORP, D.O. GARY TAKAHASHI, M.D. GUY DELOREFICE, M.D. St. Vincent Hospital and Medical Center Portland, Oregon 1. Leppert M, Burt R, Hughes JP, et al. Genetic analysis of an inherited predisposition to colon cancer in a family with a variable number of adenomatous polyps. N Engl J Med 1990;332:904– 908. 2. Zwick A, Munir M, Ryan CK, et al. Gastric adenocarcinoma and dysplasia in fundic gland polyps of a patient with attenuated adenomatous polyposis coli. Gastroenterology 1997;113:659– 663.
Reply. We read the letter by Dr. Lobitz and his associates with considerable interest. Since we found our first patient out of a large kindred with a known AAPC gene,1 we have found another family member, a 35-year-old man, who had numerous gastric fundic gland polyps carpeting the entire fundic region. Among 20 polyps removed by polypectomies, we found high-grade dysplasia in some of these
polyps.2 Based on the finding, he underwent total gastrectomy, which showed no evidence of direct extension of neoplastic process beyond the polyps with severe dysplasia. In a 11⁄2-year follow-up, there has been no evidence of metastasis. The patient cited by Dr. Lobitz et al., a 45-year-old man, did not have evidence of high-grade dysplasia in the removed polyps by us in the summer of 1996. It appears that Lobitz et al. have not found dysplasia in the biopsy specimens. Thus, it is not certain whether the primary lesion has indeed developed in the patient’s gastric fundic polyps, although it is highly suggestive, as they mentioned. The patient we described recently1 had direct invasion of carcinoma into a local blood vessel and gastric wall. It is suggested that biopsy specimens from these polyps may not be adequate for detecting high-grade dysplasia or cancer. Our present practice (W.Y.C.) is to randomly remove about 20 polyps for a thorough histological examination. In addition, gastric fundic mucosal cytology with brush should be considered in these patients. One more caution is that the endoscopist must cauterize the bleeding site after each polyp removal. Before removing an endoscope from the stomach, one must be assured that all the oozing sites are cauterized; otherwise they tend to slowly bleed to become significantly anemic in several days following the procedure. WILLIAM Y. CHEY, M.D. CHARLOTTE RYAN, M.D. University of Rochester Medical Center Rochester, New York RANDALL BURT, M.D. University of Utah Medical Center Salt Lake City, Utah 1. Zwick A, Munir M, Ryan CK, et al. Gastric adenocarcinoma and dysplasia in fundic gland polyps of a patient with attenuated adenomatous polyposis coli. Gastroenterology 1997;113:659– 663. 2. Lakshman V, Shah AN, Ryan CK, et al. The presence of dysplasia and carcinoma in gastric fundic gland polyps in patients with familial adenomatous polyposis (abstr). Gastroenterology 1997; 112:A599.
Does Growth Hormone and Glutamine Enhance Bowel Absorption? Dear Sir: When two research groups perform similar studies and report disparate results, a common reason for the differences is variations between the study protocols. This appears to be the case in the work reported by Scolapio et al.,1 who evaluated the effects of growth hormone, glutamine, and diet in patients with the short-bowel syndrome and failed to observe a major treatment effect, as we have now observed in the care of more than 200 patients. We would like to point out the differences in the protocol that was reported compared with our method of treatment.2,3 We believe the protocol used clearly favors a negative result. Patient selection and categorization are critical. Although we have now developed successful treatment protocols for a diverse population, our original studies aimed at evaluating the effect of growth hormone, glutamine, and diet on bowel adaptation, specifically nutrient absorption, were conducted in patients with a portion of colon incontinuity.
May 1998
The majority had suffered from ischemic events.2,3 In contrast, 6 of the 8 patients studied by Scolapio et al. had no colon and extremely short segments of remnant small bowel, and most (7 of 8) had Crohn’s disease. Others have previously commented on the potential differences between patients with and without mucosal disease.4 In selecting this patient group, the investigators should first optimize diet; this was not done. The composition of the oral fluid was not specified. Dietary sodium tended to be low, which could limit water absorption. The type of dietary fiber was not specified and may be deleterious. Only enteral glutamine was provided, and its absorption rate was not quantitated. Finally, the high-carbohydrate diet used in our original studies and prescribed by Scolapio et al. has been shown to be advantageous to patients with colons, but such a regimen, when applied to patients without colons, has been shown to increase ostomy output by 700 mL/day.5 Thus, not only are the patients selected by Scolapio et al. different, but the prescribed diet favored a negative effect. The investigators also performed their study in the outpatient setting, whereas our patients are closely supervised in an inpatient facility. No matter how compliant patients may appear, our experience over the past 5 years seems to indicate that the optimal responses can only be achieved with intensive 24-hour nursing and 18-hour dietitian coverage, 7 days a week. Patients receiving long-term parenteral infusions frequently manifest multiple nutrient deficiencies, and this may be found in a majority of this population. For example, we have found biochemical markers of essential fatty acid deficiency in 45% of the total parenteral nutrition (TPN)-dependent patients referred for therapy, and this deficiency is more severe in patients with Crohn’s disease.6 Deficiencies in fat soluble vitamins and minerals are also prominent, especially in patients with high-output ostomies. Detection and correction of these abnormalities are necessary if mucosal proliferation is to occur, because it has been shown in animal models that mucosal growth is significantly blunted in the face of malnutrition7 or with selective nutrient deficiencies such as essential fatty acids8 and vitamin A.9 The authors should show biochemical evidence that these deficiency states did not exist at the time of patient entry into the protocol to appropriately interpret their biopsy data. Measurement techniques and end points also varied between the two studies. We used a 7-day collection period because of the large variability in daily stool output, whereas the Mayo Clinic group only measured output for 2 days. We performed bomb calorimetry in both food and stool samples; Scolapio et al. used D-xylose absorption as a measure of total carbohydrate absorption. Finally, our lead-in periods were performed under close supervision to ensure that the diet ingested during the 3-week period before the balance study was similar to that ingested throughout the study. Given these protocol differences, Scolapio et al. observed improvement in nutrient absorption in 3 or 4 of their 8 patients. In contrast, 60% of 45 patients we have treated with ,50 cm jejunum-ileum and a portion of colon incontinuing—an anatomic condition cited by the authors as requiring long-term parenteral support—could be weaned from intravenous nutrition.3 Approximately one half of this total group remains independent of TPN at 2 years of follow-up. Because home nutritional support costs approximately $100,000/yr (not including hospitalizations), weaning patients from TPN is a major cost saving that clearly dwarfs the small cost of growth hormone or other bowel growth factors that are being developed. All of our studies have been performed under the auspices of the Food and Drug Administration (FDA), and we are now entering the phase III stage of this trial. Not all patients are suitable candidates for
CORRESPONDENCE
1111
bowel rehabilitation therapy. Of the 8 patients studied by Scolapio et al., only 3 would be eligible for our randomized trial designed and approved by the investigators, sponsors, and FDA. Patients with extremely short segments of small bowel and no colon will require transplantation, not growth factors, if the goal is to wean them from TPN. Bowel rehabilitation should be compared with physical therapy following hip replacement; for optimal results, patient selection is critical and the rehabilitation effort must be early, constant, consistent, and closely supervised. In an era when outcome evaluation and cost-effective care are important, such attention to details is crucial for success. Statement of financial interests: Research supported by grants from the National Institutes of Health, Food and Drug Administration, and companies involved in the sales of growth hormone (Genentech, Pharmacia-Upjohn, Eli Lilly) and nutrient formulations (Ross Laboratories, Pharmacia-Upjohn). Drs. Byrne and Wilmore are stock holders in the Nutritional Restart Center. Dr. Wilmore shares interests in patients assigned to the Brigham and Women’s Hospital pertaining to parenteral solutions and diets that contain L-glutamine and the use of growth hormone and glutamine to enhance nutrient absorption. THERESA BYRNE, Ph.D., R.D. DOUGLAS WILMORE, M.D. Department of Surgery Brigham and Women’s Hospital Harvard Medical School Boston, Massachusetts 1. Scolapio JS, Camilleri M, Fleming CR, et al. Effect of growth hormone, glutamine, and diet on adaptation in short-bowel syndrome: a randomized, controlled study. Gastroenterology 1997;113: 1074–1081. 2. Byrne TA, Morrissey T, Nattakom T, et al. Growth hormone, glutamine and modified diet enhance nutrient absorption in patients with severe short bowel syndrome. J Parenter Enter Nutr 1995;19:296–302. 3. Wilmore DW, Lacey JM, Soultanakis RP, et al. Factors predicting a successful outcome after pharmacological bowel compensation. Ann Surg 1997;226:288–293. 4. Kapadia CR. The short bowel syndrome: new vistas. Gastroenterology 1996;110:1318–1319. 5. Nordgaard I, Hansen BS, Mortensen PB. Colon as a digestive organ in patients with short bowel. Lancet 1994;343:373–376. 6. Persinger R, Byrne TA, Browning B, et al. Evidence of essential fatty acid deficiency in patients receiving long-term parenteral nutrition despite use of fat emulsion. J Parenter Enter Nutr 1995;19(Suppl): 205. 7. Ziegler TR, Desai SAS, Gu LH, et al. Effects of growth hormone (GH) administration on rat intestinal mass and gut IGF system in RNAs in the fed and fasted states (abstr). Gastroenterology 1997;112: A423. 8. Hart MH, Grandjean CJ, Park JHY, et al. Essential fatty acid deficiency and postresection mucosal adaptation in the rat. Gastroenterology 1988;94:682–687. 9. Swartz-Basile DA, Rubin DC, Levin MS. Vitamin A status influences intestinal adaptation (abstr). Gastroenterology 1997;112:A408.
Reply. The letter by Drs. Byrne and Wilmore emphasizes many of the points regarding patient selection that were already made in the discussion section of our paper.1 We would like to offer the following comments regarding points of disagreement. 1. The inclusion of patients without colonic continuity was necessary because there was no basis for their exclusion based on previous uncontrolled studies. In their previous paper, Byrne et al. referred to a beneficial response to treatment in 2 patients with short-bowel
CORRESPONDENCE AAPC: Are Current Screening Recommendations Enough? Dear Sir: In 1990 a large kindred with a known mutation of the attenuated adenomatous polyposis coli (AAPC) gene and varied phenotypic expression was described.1 Frequent surveillance for members carrying the mutation has been recommended. In August 1997 a case report described malignant transformation of a fundic gland polyp in 1 of the family members. Previously, it was considered that fundic gland polyps had little or no chance of developing malignancy. As a result of this case report, it was recommended that fundic gland polyps be biopsied as an adjunct to prior screening recommendations.2 Over the last 5 years, the brother of the patient described in the case report has been followed up at our facility. He has undergone surveillance every 1–2 years via esophagogastroduodenoscopy, colonoscopy, and appropriate biopsies. His most recent study in August of 1997 revealed several small mammilations throughout the colon (but no larger polyps or cancer) and a sheet of hyperplastic polyps in the gastric fundus. Biopsies of the fundic gland polyps and gastric antrum proved unrevealing. A barium swallow and small bowel followthrough in 1994 showed no sign of polyps in the small bowel. In September 1997, the patient presented with right upper quadrant abdominal pain, generalized fatigue, and early satiety. Chemistries showed elevated alkaline phosphatase and aspartine transferase levels. Computed topography of the abdomen showed multiple densities in the liver suggestive of malignancy. Needle biopsy confirmed the diagnosis of moderately differentiated adenocarcinoma. With no evidence of primary lesion, endoscopic ultrasound examination of the gastric fundus was performed. It proved unremarkable. The implication that a second family member in this kindred may have developed a malignancy with no discernible source despite careful screening suggests that current screening recommendations may not be sufficient. Further study of other modalities would seem warranted to prevent similar unexpected metastases. JOHN LOBITZ, M.D. MICAH THORP, D.O. GARY TAKAHASHI, M.D. GUY DELOREFICE, M.D. St. Vincent Hospital and Medical Center Portland, Oregon 1. Leppert M, Burt R, Hughes JP, et al. Genetic analysis of an inherited predisposition to colon cancer in a family with a variable number of adenomatous polyps. N Engl J Med 1990;332:904– 908. 2. Zwick A, Munir M, Ryan CK, et al. Gastric adenocarcinoma and dysplasia in fundic gland polyps of a patient with attenuated adenomatous polyposis coli. Gastroenterology 1997;113:659– 663.
Reply. We read the letter by Dr. Lobitz and his associates with considerable interest. Since we found our first patient out of a large kindred with a known AAPC gene,1 we have found another family member, a 35-year-old man, who had numerous gastric fundic gland polyps carpeting the entire fundic region. Among 20 polyps removed by polypectomies, we found high-grade dysplasia in some of these
polyps.2 Based on the finding, he underwent total gastrectomy, which showed no evidence of direct extension of neoplastic process beyond the polyps with severe dysplasia. In a 11⁄2-year follow-up, there has been no evidence of metastasis. The patient cited by Dr. Lobitz et al., a 45-year-old man, did not have evidence of high-grade dysplasia in the removed polyps by us in the summer of 1996. It appears that Lobitz et al. have not found dysplasia in the biopsy specimens. Thus, it is not certain whether the primary lesion has indeed developed in the patient’s gastric fundic polyps, although it is highly suggestive, as they mentioned. The patient we described recently1 had direct invasion of carcinoma into a local blood vessel and gastric wall. It is suggested that biopsy specimens from these polyps may not be adequate for detecting high-grade dysplasia or cancer. Our present practice (W.Y.C.) is to randomly remove about 20 polyps for a thorough histological examination. In addition, gastric fundic mucosal cytology with brush should be considered in these patients. One more caution is that the endoscopist must cauterize the bleeding site after each polyp removal. Before removing an endoscope from the stomach, one must be assured that all the oozing sites are cauterized; otherwise they tend to slowly bleed to become significantly anemic in several days following the procedure. WILLIAM Y. CHEY, M.D. CHARLOTTE RYAN, M.D. University of Rochester Medical Center Rochester, New York RANDALL BURT, M.D. University of Utah Medical Center Salt Lake City, Utah 1. Zwick A, Munir M, Ryan CK, et al. Gastric adenocarcinoma and dysplasia in fundic gland polyps of a patient with attenuated adenomatous polyposis coli. Gastroenterology 1997;113:659– 663. 2. Lakshman V, Shah AN, Ryan CK, et al. The presence of dysplasia and carcinoma in gastric fundic gland polyps in patients with familial adenomatous polyposis (abstr). Gastroenterology 1997; 112:A599.
Does Growth Hormone and Glutamine Enhance Bowel Absorption? Dear Sir: When two research groups perform similar studies and report disparate results, a common reason for the differences is variations between the study protocols. This appears to be the case in the work reported by Scolapio et al.,1 who evaluated the effects of growth hormone, glutamine, and diet in patients with the short-bowel syndrome and failed to observe a major treatment effect, as we have now observed in the care of more than 200 patients. We would like to point out the differences in the protocol that was reported compared with our method of treatment.2,3 We believe the protocol used clearly favors a negative result. Patient selection and categorization are critical. Although we have now developed successful treatment protocols for a diverse population, our original studies aimed at evaluating the effect of growth hormone, glutamine, and diet on bowel adaptation, specifically nutrient absorption, were conducted in patients with a portion of colon incontinuity.
May 1998
The majority had suffered from ischemic events.2,3 In contrast, 6 of the 8 patients studied by Scolapio et al. had no colon and extremely short segments of remnant small bowel, and most (7 of 8) had Crohn’s disease. Others have previously commented on the potential differences between patients with and without mucosal disease.4 In selecting this patient group, the investigators should first optimize diet; this was not done. The composition of the oral fluid was not specified. Dietary sodium tended to be low, which could limit water absorption. The type of dietary fiber was not specified and may be deleterious. Only enteral glutamine was provided, and its absorption rate was not quantitated. Finally, the high-carbohydrate diet used in our original studies and prescribed by Scolapio et al. has been shown to be advantageous to patients with colons, but such a regimen, when applied to patients without colons, has been shown to increase ostomy output by 700 mL/day.5 Thus, not only are the patients selected by Scolapio et al. different, but the prescribed diet favored a negative effect. The investigators also performed their study in the outpatient setting, whereas our patients are closely supervised in an inpatient facility. No matter how compliant patients may appear, our experience over the past 5 years seems to indicate that the optimal responses can only be achieved with intensive 24-hour nursing and 18-hour dietitian coverage, 7 days a week. Patients receiving long-term parenteral infusions frequently manifest multiple nutrient deficiencies, and this may be found in a majority of this population. For example, we have found biochemical markers of essential fatty acid deficiency in 45% of the total parenteral nutrition (TPN)-dependent patients referred for therapy, and this deficiency is more severe in patients with Crohn’s disease.6 Deficiencies in fat soluble vitamins and minerals are also prominent, especially in patients with high-output ostomies. Detection and correction of these abnormalities are necessary if mucosal proliferation is to occur, because it has been shown in animal models that mucosal growth is significantly blunted in the face of malnutrition7 or with selective nutrient deficiencies such as essential fatty acids8 and vitamin A.9 The authors should show biochemical evidence that these deficiency states did not exist at the time of patient entry into the protocol to appropriately interpret their biopsy data. Measurement techniques and end points also varied between the two studies. We used a 7-day collection period because of the large variability in daily stool output, whereas the Mayo Clinic group only measured output for 2 days. We performed bomb calorimetry in both food and stool samples; Scolapio et al. used D-xylose absorption as a measure of total carbohydrate absorption. Finally, our lead-in periods were performed under close supervision to ensure that the diet ingested during the 3-week period before the balance study was similar to that ingested throughout the study. Given these protocol differences, Scolapio et al. observed improvement in nutrient absorption in 3 or 4 of their 8 patients. In contrast, 60% of 45 patients we have treated with ,50 cm jejunum-ileum and a portion of colon incontinuing—an anatomic condition cited by the authors as requiring long-term parenteral support—could be weaned from intravenous nutrition.3 Approximately one half of this total group remains independent of TPN at 2 years of follow-up. Because home nutritional support costs approximately $100,000/yr (not including hospitalizations), weaning patients from TPN is a major cost saving that clearly dwarfs the small cost of growth hormone or other bowel growth factors that are being developed. All of our studies have been performed under the auspices of the Food and Drug Administration (FDA), and we are now entering the phase III stage of this trial. Not all patients are suitable candidates for
CORRESPONDENCE
1111
bowel rehabilitation therapy. Of the 8 patients studied by Scolapio et al., only 3 would be eligible for our randomized trial designed and approved by the investigators, sponsors, and FDA. Patients with extremely short segments of small bowel and no colon will require transplantation, not growth factors, if the goal is to wean them from TPN. Bowel rehabilitation should be compared with physical therapy following hip replacement; for optimal results, patient selection is critical and the rehabilitation effort must be early, constant, consistent, and closely supervised. In an era when outcome evaluation and cost-effective care are important, such attention to details is crucial for success. Statement of financial interests: Research supported by grants from the National Institutes of Health, Food and Drug Administration, and companies involved in the sales of growth hormone (Genentech, Pharmacia-Upjohn, Eli Lilly) and nutrient formulations (Ross Laboratories, Pharmacia-Upjohn). Drs. Byrne and Wilmore are stock holders in the Nutritional Restart Center. Dr. Wilmore shares interests in patients assigned to the Brigham and Women’s Hospital pertaining to parenteral solutions and diets that contain L-glutamine and the use of growth hormone and glutamine to enhance nutrient absorption. THERESA BYRNE, Ph.D., R.D. DOUGLAS WILMORE, M.D. Department of Surgery Brigham and Women’s Hospital Harvard Medical School Boston, Massachusetts 1. Scolapio JS, Camilleri M, Fleming CR, et al. Effect of growth hormone, glutamine, and diet on adaptation in short-bowel syndrome: a randomized, controlled study. Gastroenterology 1997;113: 1074–1081. 2. Byrne TA, Morrissey T, Nattakom T, et al. Growth hormone, glutamine and modified diet enhance nutrient absorption in patients with severe short bowel syndrome. J Parenter Enter Nutr 1995;19:296–302. 3. Wilmore DW, Lacey JM, Soultanakis RP, et al. Factors predicting a successful outcome after pharmacological bowel compensation. Ann Surg 1997;226:288–293. 4. Kapadia CR. The short bowel syndrome: new vistas. Gastroenterology 1996;110:1318–1319. 5. Nordgaard I, Hansen BS, Mortensen PB. Colon as a digestive organ in patients with short bowel. Lancet 1994;343:373–376. 6. Persinger R, Byrne TA, Browning B, et al. Evidence of essential fatty acid deficiency in patients receiving long-term parenteral nutrition despite use of fat emulsion. J Parenter Enter Nutr 1995;19(Suppl): 205. 7. Ziegler TR, Desai SAS, Gu LH, et al. Effects of growth hormone (GH) administration on rat intestinal mass and gut IGF system in RNAs in the fed and fasted states (abstr). Gastroenterology 1997;112: A423. 8. Hart MH, Grandjean CJ, Park JHY, et al. Essential fatty acid deficiency and postresection mucosal adaptation in the rat. Gastroenterology 1988;94:682–687. 9. Swartz-Basile DA, Rubin DC, Levin MS. Vitamin A status influences intestinal adaptation (abstr). Gastroenterology 1997;112:A408.
Reply. The letter by Drs. Byrne and Wilmore emphasizes many of the points regarding patient selection that were already made in the discussion section of our paper.1 We would like to offer the following comments regarding points of disagreement. 1. The inclusion of patients without colonic continuity was necessary because there was no basis for their exclusion based on previous uncontrolled studies. In their previous paper, Byrne et al. referred to a beneficial response to treatment in 2 patients with short-bowel