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Nutritional Support for Crohn's Disease
00394109/01 $15.00
CROHNS DISEASE
+ .OO
NUTRITIONAL SUPPORT FOR CROHN’S DISEASE Howard K. Song, MD, and Gordon P. Buzby, MD
Disordered nutrition has been associated with Crohn’s disease since the initial description of the disease in 1932.13Crohn recognized weight loss, which occurs in as many as 76% of patients, as a predominant feature of the disease, and subsequent studies have demonstrated that specific deficiencies in amino acids and micronutrients also are comm ~ nDespite . ~ ~ the high frequency of malnutrition among patients with Crohn’s disease, monitoring of the nutritional status of these patients often is insufficient.2*l7 Systematic nutritional assessment should be a routine part of the management of all patients with Crohn‘s disease, to guide nutritional intervention as supportive therapy. Some trials have focused on the potential usefulness of nutritional intervention as a primary anti-inflammatory therapy for patients with Crohn’s disease. MALNUTRITION IN CROHN’S DISEASE
Origins Malnutrition, in general, may result from several basic mechanisms: inadequate intake, malabsorption, increased losses, increased requirements, and drug-nutrient interactions. The cause of malnutrition in Crohn’s disease is usually multifactorial, and factors representing each of these basic mechanisms contribute to the high prevalence of nutritional deficiency among these patients.16,26 Common factors leading to malnu-
From the Department of Surgery, University of Pennsylvania Medical Center (HKS); and Clinical Nutrition Support Services, Hospital of the University of Pennsylvania (GPB), Philadelphia, Pennsylvania
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Table 1. CAUSES OF MALNUTRITION IN PATIENTS WITH CROHN’S DISEASE Basic Mechanism
Inadequate intake Malabsorption
Increased losses Increased requirements Drug-nutrient interactions
In Crohn’s Disease
Anorexia, fear of abdominal pain after eating Loss of absorptive surface from disease or surgery; mucosal cell disease; stagnant-loop syndrome from strictures, fistulas, or surgical blind loops; lymphangiectasia; rapid gastrointestinal transit Exudation from mucosa, fistulas, interrupted enterohepatic circulation Active inflammation, sepsis Sulfasalazine, corticosteroids, antibiotics
Data from references 16,26,38, and 60
trition in patients with Crohn’s disease are summarized in Table 1. Patients with Crohn’s disease commonly have anorexia or limit their food intake because of abdominal pain or diarrhea associated with eating. Malabsorption of nutrients can result from loss of absorptive surface area secondary to mucosal involvement with disease, shortbowel syndrome, terminal ileal resection, stagnant loop syndrome, lymphangiectasia, and rapid gastrointestinal transit. Exudation associated with inflammation, fistulas, and interrupted enterohepatic circulation can lead to protein, water, electrolyte, and fatty-acid losses. Nutritional requirements are increased in patients with active inflammation, infection, sepsis, and accelerated mucosal cell turnover. Several drugs commonly used in the treatment of Crohn’s disease have important effects on nutrient absorption and use. Sulfasalazine decreases folate absorption; corticosteroids alter protein metabolism, inhibit calcium absorption, and induce magnesemia; antibiotics modify gut floras and thereby can affect vitamin K metabolism. Specific Deficiencies
The specific nutritional deficiencies in patients with Crohn’s disease are detailed in Table 2. Weight loss has been regarded as a predominant feature of Crohn’s disease since its first description and occurs in as many as 76% of patients in some seriesz0Even in a subset of patients without active disease, as many as 20% may be more than 10% below ideal In pediatric patients, growth retardation often precedes clinical onset of Crohn’s disease. Approximately one third of children with active disease have delayed linear growth and delayed onset of Although absorption of carbohydrates usually is preserved in patients with Crohn’s disease, protein and fat absorption are decreased, which can lead to specific nutrient Amino-acid deficiencies contribute to hypoalbuminemia and hypoproteinemia. Intestinal protein loss, reduced hepatic protein synthesis, increased catabolism, and anorexia also promote this condition, making serum albumin levels more
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Table 2. PREVALENCE OF NUTRITIONAL DEFICIENCIES AMONG PATIENTS WITH CROHN'S DISEASE Deficiency
Prevalence (%)
Weight loss Growth retardation Hypoalbuminemia Anemia Iron Folate Vitamin Blz Calcium Magnesium Potassium zinc
65-76 40 25-80 60-80 39 54 48 13
14-88 6-20 40-50
Data from references 20-21 and 38
a marker of disease activity than nutritional status.60Impaired fat absorption in some patients, exacerbated by interrupted enterohepatic circulation, may contribute to decreased absorption and deficiencies of calcium, magnesium, and zinc.31 Anemia in patients with Crohn's disease is common, and its cause may be m~ltifactorial.'~ Iron, folate, and vitamin B,, deficiencies are all common. Also, patients with active disease may have anemia related to chronic inflammation even in the absence of a specific nutritional deficit. Patients with Crohn's disease also may have deficiencies in vitamins C, D, K, and trace metals, such as selenium. Deficiencies of these nutrients usually are not clinically overt.6O Nutritional Assessment of Patients with Crohn's Disease
Timely recognition of malnutrition allows for early nutritional intervention and correction of deficits, which is important in the care of surgical patients who have a high prevalence of unrecognized malnutrit i ~ nAlso, . ~ presurgical nutritional support for severe malnutrition reduces postsurgical complications related to malnutrition.10,63 The nutritional assessment of all these patients begins with detailed history taking and a physical examination. Specific areas to address in this patient population include current disease activity; previous surgeries; and symptoms related to Crohn's disease, such as abdominal pain, enteric fistulas, bowel obstruction, diarrhea, steatorrhea, hematochezia, and fever, which may affect nutrient intake, losses, and metabolism. Changes in appetite, food intake, and weight should be documented routinely. Various methods are available to assess the adequacy of dietary intake, including 24-hour recall of intake and prospectively recorded food records and calorie counts.28Medications should be reviewed for drug-nutrient interactions. These patients should be exam-
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ined for physical signs of vitamin and trace-element deficiencies and muscle wasting more typical of protein-energy malnutrition. Children with Crohn's disease commonly have delays in growth and development, making monitoring of these processes important. Ideally, height, weight, sexual staging, and bone age are monitored regularly during the course of care.I7 Despite this, some studies have found severe underrecording of growth parameters by physicians during the routine followup of children with Crohn's disease.2,l7 Laboratory studies are a useful adjunct in the nutritional assessment of patients with Crohn's disease. A complete blood count is useful given the high prevalence of anemia among these patients. Iron, folate, and vitamin BIZmeasurements are necessary to determine the specific nutrient deficiency responsible for anemia after it is recognized. Lymphopenia related to protein deficiency also may be detected on screening complete blood Measurement of serum electrolytes also is important given the high prevalence of electrolyte deficiencies, particularly among patients presenting with surgical complications of Crohn's disease, such as bowel obstruction or enterocutaneous fistulas. Although the levels of serum proteins, such as albumin, prealbumin, and transferrin commonly are decreased, the cause of hypoproteinemia in patients with Crohn's disease is usually multifactorial and may not be related only to specific amino-acid deficiencies. Dissatisfaction with biochemical techniques has led to the use of anthropometric data for the nutritional assessment of at-risk patients, including patients with Crohn's disease." 27, 33, 40 Skinfold and limbcircumference measurements are performed easily, and when these data are related to the amount of adipose tissue and lean body mass using standard tables, they better reflect the nonspecific malnourishment typically encountered in patients with Crohn's disease.60Finally, several multivariant analyses of nutritional parameters have been performed to develop formulas that relate the risk for postsurgical complications with presurgical nutritional status. One such formula is the prognostic nutrition index, which is calculated as follows: PNI = 158 - 16.6 (Alb) - 0.78 (TSF) - 0.2 (TFN) - 5.8 (DH) where PNI is the prognostic nutrition index, Alb is serum albumin (g/dL), TSF is triceps skinfold (mm), TFN is serum transferrin (mg/dL), and DH is delayed cutaneous hypersensitivity graded from 0 to 2.11Although the prognostic nutrition index has not been validated prospectively for the presurgical evaluation of patients with Crohn's disease per se, application of this nutritional assessment prospectively to 100 nonemergent general surgical patients was highly predictive of postsurgical complications." NUTRITION AS SUPPORTIVE THERAPY FOR CROHN'S DISEASE
Nutritional therapy has a potential role in the treatment of Crohn's disease, in several settings, as a supportive and primary therapy. Nutri-
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tional therapy is indicated as a supportive measure to (1) improve the nutritional status of malnourished patients; (2) meet the nutritional requirements of patients being treated for active Crohn’s disease medically and with bowel rest; (3) perioperatively reduce protein loss and morbidity related to surgery; and, (4) manage complications of surgical therapy for Crohn‘s disease, such as enterocutaneous fistulas and shortbowel syndrome. Improving Nutritional Status
Patient education and dietary manipulation are early supportive measures that may be used to improve the nutritional status of malnourished ~atients.3~ Properly educated patients are better able to monitor dietary intake and continuously assess their own risk for malnutrition. Reduction of dietary bulk and fat may decrease symptoms related to Crohn’s disease, such as abdominal pain, diarrhea, and steatorrhea, that adversely affect patients’ nutritional status by leading to anorexia and malabsorption.’ Restriction of dietary fat necessitates supplementation with other foods to maintain adequate caloric intake. Carbohydrates are a useful source of calories in these patients because they are readily absorbed. High dietary protein intake also is important to maintain weight, replace protein losses, and preserve skeletal and respiratory muscle function. Multivitamin supplements also may be necessary to prevent or replace micronutrient deficiencies. Nutritional therapy may have an important role in the supportive treatment of children with Crohn’s disease who commonly suffer from delayed linear growth and development. Multiple studies have demonstrated that growth and development resume in these patients when nutritional therapy is instituted before epiphyseal closure.39,45 Nutritional supplementation may be economically and conveniently administered by liquid formulations containing a carbohydrate source and hydrosylated proteins or free amino acids. Elemental formulas may be specifically indicated for patients with impaired absorption related to small-bowel involvement with disease, short-bowel syndrome, and diarrhea. Although more easily absorbed, elemental formulas are unpalatable and typically are administered through fine-bore nasogastric feeding tubes, which are generally well tolerated. Some form of oral or enteral feeding is usually suitable for most patients with Crohn’s disease who require supplementation to improve their nutritional status. Adjuvant Therapy for Active Crohn’s Disease
The optimal primary treatment of Crohn‘s disease, and the role that bowel rest may have in allowing more rapid resolution of acute attacks, are debatable. Although bowel rest has been advocated for the primary treatment of acute Crohn’s disease, multiple studies have shown no
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primary therapeutic effect or poorly sustained results in patients treated 48 On primarily with bowel rest and total parenteral nutrition (TPN).36, the other hand, investigators generally agree that a synergistic effect occurs when nutritional supplementation is given to patients receiving steroid therapy for active Crohn's disease. TI" has been found to prevent protein loss and preserve skeletal and respiratory muscle function in such patients.12 Administration of total enteral nutrition to malnourished patients being treated for active Crohn's disease has been found to allow modest weight gain.55 Nutritional Therapy During the Perioperative Period
Surgical patients are predisposed to malnutrition, which also is true of patients with Crohn's disease. As many as 50% of surgical patients 34 Further underscorhave malnutrition that is commonly unre~ognized.~, ing the importance of nutritional assessment and support in the care of surgical patients, several studies have demonstrated a close association between malnutrition and postsurgical morbidity.*The broad availability of TPN and increased awareness of perioperative morbidity secondary to nutrition-related complications has led to the widespread application of perioperative TPN with the intent of reducing postsurgical complications. This approach has been validated by several large, prospective, randomized studies that have demonstrated that severely malnourished general surgical patients receiving a 7-day to 10-day course of TI" presurgically benefit from a reduction in major, noninfectious complications.lO,63 This benefit was not demonstrated in well-nourished or only moderately malnourished patients. Series studying perioperative TPN specifically for the care of patients with inflammatory bowel disease have been somewhat less persuasive. These smaller studies have failed to demonstrate a reduction in surgical morbidity in patients with active Crohn's disease treated presurgically with TPN. A prospective study of 19 clinically malnourished patients who had acute exacerbations of Crohn's disease showed that short courses of TI" in these patients prevent protein loss and result in significant improvements in skeletal and respiratory muscle function.12 Also, patients with Crohn's disease who have low serum protein levels in one study were found to have an approximately fivefold increase in surgical complication rate compared with patients with normal serum protein levels.42These findings support the concept that supportive nutritional therapy may have efficacy in the reduction of surgical morbidity in malnourished patients with Crohn's disease. In the absence of large, prospective clinical trials that specifically address this issue, presurgical administration of short courses of TPN to severely malnourished patients for whom surgery may be safely delayed is a rational use of supportive nutritional therapy. Also, if surgery must be *References6, 14, 29, 44, 46-47, 53, 57, and 68.
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delayed to address other issues (e.g., preparing the bowel, decreasing fistula output, and improving peristomal inflammation), then nutritional support should be provided to prevent further deterioration during mandatory presurgical fasting. Nutritional Therapy for Enterocutaneous Fistulas
Enterocutaneous fistulas in patients with Crohn‘s disease arise in two settings.32,50 Type 1 fistulas arise from an area of bowel affected by active Crohn’s disease. Type 2 fistulas arise from a site of anastomosis after surgical resection. Type 1 fistulas rarely heal with conservative measures and typically mandate surgery. Type 2 fistulas, on the other 50 This hand, commonly heal with bowel rest and nutritional support typically is given in the form of TPN, but elemental enteral nutrition may be used for distal fistulas because these diets are almost entirely absorbed by the first 100 cm of small intestine. Nutritional Therapy for Short-Bowel Syndrome
Short-bowel syndrome is the clinical syndrome of diarrhea, fluid and electrolyte disturbances, and malabsorption that follows extensive small-bowel resection.* Despite the current emphasis on conservative surgery for Crohn’s disease, surgery for this disorder is the most common cause of short-bowel syndrome in adult populations.61Short-bowel syndrome is of concern after extensive small-bowel resection for Crohn’s disease because such resections often lead to loss of the ileocecal valve. Many patients with an intact ileocecal valve and pylorus can resume nearly normal gut function after the bowel adapts by assuming greater absorptive capacity. In such patients, segments of jejunum as short as In 30.5 cm have been reported to eventually support enteral patients lacking an ileocecal valve, however, approximately 100 cm of bowel may be necessary to maintain adequate enteral f u n ~ t i o n . ~ When massive or serial resections leave a patient with less than this amount, inadequate intestinal absorptive area and short transit time lead to incomplete digestion and absorption of carbohydrates, fats, and proteins. Loss of the ileum causes malabsorption of vitamin BIZ and interruption of the enterohepatic circulation, which exacerbates fat malabsorption and steatorrhea. Fat malabsorption and steatorrhea lead to wasting of the fat-soluble vitamins A, D, E, and K, and increased excretion of calcium and magnesium, which results in severe vitamin and electrolyte deficiencies. Patients with short-bowel syndrome require replacement of fluid and electrolytes, provision of adequate calories, and supplementation of inadequately absorbed nutrients and minerals. Short-bowel syndrome was one of the first indications for which TPN was originally developed, and for these patients, TPN is life~aving.~~ TPN should be administered
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beginning immediately after surgery to prevent protein losses related to the catabolic effects of surgery and to nutritionally support the patient during healing and bowel adaptation” After the immediate postsurgical period, assessment of the patient’s enteral function is begun. Adaptation by the bowel occurs over months or years, during which the patient’s TPN regimen is tailored to replace specific nutritional constituents not absorbed from the patient’s oral feedings. Oral intake usually is begun in the form of an isotonic elemental formula to maximize absorption and minimize diarrhea and steatorrhea related to malabsorption. These symptoms may be controlled further with antimotility agents, such as loperamide. Surviving patients with marginal bowel function must maintain a delicate balance between their disorder and the nutritional regimen necessary to sustain them. Illnesses may increase metabolic requirements, and recurrent Crohn‘s disease may diminish bowel function, affecting patients’ requirements for supportive nutritional therapy. These patients should be followed up closely so that specific nutritional and metabolic derangements may be corrected as they occur. NUTRITION AS PRIMARY THERAPY FOR CROHN’S DISEASE
Intraluminal gut antigens, derived from dietary intake and bowel flora, have been widely proposed to have a role in the pathogenesis of Crohn’s disease.67This suspicion led to nutritional interventions that may reduce antigenic load delivered to the intestinal mucosa and thereby act as a primary anti-inflammatory the rap^.^ The initial enthusiasm for the widespread use of nutrition as a primary therapy for Crohn‘s disease has waned with the advent of carefully controlled studies demonstrating the superiority of corticosteroids in the treatment of active Crohn‘s disease, but indications for the selective use of primary nutritional therapy for Crohn’s disease are emerging as the association between patients’ nutritional status and their level of disease activity has become better appreciated. Parenteral Nutrition for Acute Crohn’s Disease
TPN has been proposed to act as a primary therapy for active Crohn’s disease by “resting” the bowel from absorptive function and allowing healing of affected areas.l5 This rationale has been challenged in a prospective multicenter trial and is no longer thought to be ~ a l i d . 2 ~ When TPN was used as sole therapy for Crohn‘s disease in one study, patients had a 36% resection rate after one year and a fourfold increase in relapse rate.@Therefore, TPN does not have a primary therapeutic role in the treatment of active Crohn’s disease. Attention has been focused on the potential use of enteral nutrition in this setting.
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Enteral Nutrition for Acute Crohn’s Disease Enteral nutrition has several effects that are of potential benefit in the treatment of Crohn‘s disease. Elemental enteral diets have been proposed to reduce the antigenic exposure of the intestinal mucosa by altering the bowel flora and by replacing the complex protein antigens present in normal foodstuffs with free amino acids or ~ligopeptides.~~ Another potential advantage of enteral nutrition over parenteral nutrition is the direct nourishment of the intestinal mucosa by the feeding solution.=,59 This is thought to lead to improved mucosal integrity and reduced protein losses. Provision of glutamine holds great promise in this regard because of its trophic effects on the small intestine and 30, 58 Epidermal proposed beneficial effects on gut immune fun~tion.~, growth factor also induces intestinal growth and repair and exerts a 49, 52 Nucleotides have protective effect in animal models of been shown to stimulate intestinal growth and have been proposed to modulate intestinal repair after injury.62,64 More studies are necessary to determine the role of these and other trophic factors in the management of patients with Crohn‘s disease. Conventional enteral nutrition for the treatment of active Crohn’s disease has been evaluated in several prospective, randomized, controlled trials.l8*24 Although efficacy of enteral nutrition has been shown, relapse of disease activity has been seen in many patients within several months of stopping the enteral nutritional therapy.19Also, none of these studies have demonstrated an advantage of elemental or whole-proteinbased diets over steroid therapy in the treatment of active Crohn’s disease.18A meta-analysis of these studies supports the overall conclusion that steroid therapy is more effective than enteral nutrition in the management of active Crohn’s disease.24Despite this, enteral nutrition is a reasonable secondary therapeutic option for patients with active Crohn’s disease who are intolerant or resistant to steroids; as many as 40% of these patients achieve a therapeutic e f f e ~ t . ~
Enteral Nutrition for the Maintenance of Clinical Remission An emerging indication for enteral nutrition in the management of patients with Crohn’s disease is in the maintenance of disease remission. Several smaller studies have identified a beneficial effect of supplementary enteral nutrition without restriction of normal diet in patients treated between acute attack^.^, 25, 51, 66 Supplementary enteral nutrition provided orally or through nasogastric feeding tubes nocturnally has been associated with prolongation of remission and, in adolescent and pediatric patients, improved linear growth. The mechanism by which enteral nutrition mediates reduction in intestinal inflammation is unclear. Bowel rest does not have a role because enteral nutrition was provided as a supplement without restric-
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tion of normal oral intake. Rather, clinical remission has been correlated with improvements in nutritional status, suggesting that the anti-inflammatory effects of enteral nutrition in this setting are primarily nutritional.%Whether these effects are dependent on improving the overall nutritional state or on the provision of a specific micronutrient, such as glutamine, is unknown. Irrespective of the mechanism, results of early clinical trials using this approach have been encouraging and warrant larger, prospectively performed studies in the future. In the interim, selective use of supplementary enteral nutrition for the maintenance of remission of Crohn’s disease seems reasonable, particularly in children, in whom improvements in patients’ growth and development would be expected to further enhance their well-being.
SUMMARY
Nutritional considerations are intimately associated with Crohn’s disease. Food antigens and dietary factors have been postulated to have a role in its pathogenesis, and the disease leads to decreased absorptive capacity of the gut. Malnutrition is a common manifestation of Crohn’s disease, necessitating close monitoring of patients and rapid nutritional intervention to correct deficiencies. The indications for supportive nutritional therapy are well defined and include measures to improve patients’ nutritional status and growth and development; decrease perioperative complications; and manage complications of Crohn‘s disease, including enterocutaneous fistulas and short-bowel syndrome. Nutritional therapy as a first-line treatment of Crohn‘s disease is controversial. Although enteral nutrition has been found to have efficacy in this setting, steroid therapy is the gold standard treatment of acute Crohn‘s disease, with enteral nutrition reserved for steroid-resistant or steroid-intolerant patients. An emerging use of supplementary enteral nutrition is in the maintenance of Crohn’s disease remission. Interestingly, this benefit seems to be associated with improvement in patients’ nutrition, suggesting a relationship between nutritional status and disease activity. Further insight into this field, including the potential of micronutrients to promote trophic, healing, and immunomodulatory effects on the gut, may lead to novel and efficacious treatments of this disease.
References 1. Alexander-Williams J, Haynes IG: Up-to-date management of small-bowel Crohn’s disease. Adv Surg 20245-264, 1987 2. Barton JR, Ferguson A Failure to record variables of growth and development in children with inflammatory bowel disease. BMJ 298:423439, 1989 3. Belli DC, Seidman E, Bonthillier L, et al: Chronic intermittent elemental diet improves growth failure in children with Crohn’s disease. Gastroenterology 94:603410,1988 4. Bergren CT: Indications for parenteral nutrition. In Shikora SA, Blackbum GL (eds):
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Nutrition Support: Theory and Therapeutics. New York, Chapman & Hall, 1997, pp 113-119 5. Bemstein CN, Shanahan F Critical appraisal of enteral nutrition as primary therapy in adults with Crohn’s disease [see comments]. Am J Gastroenterol91:2075-2079,1996 6. Bistrian BR, Blackbum GL, Hallowell E, et al: Protein status of general surgical patients. JAMA 230:858-860, 1974 7. Blackbum GL, Bistrian BR, Maini BS, et al: Nutritional and metabolic assessment of the hospitalized patient. JPEN J Parenter Enteral Nutr 1:ll-22, 1977 8. Block GE, Hurst R D Complications of the Surgical Treatment of Ulcerative Colitis and Crohn’s Disease. Baltimore, Williams & Wilkins, 1995 9. Burke DJ, Alverdy JC, Aoys E, et al: Glutamine-supplemented total parenteral nutrition improves gut immune function. Arch Surg 1241396-1399, 1989 10. Buzby GP, et al: Perioperative total parenteral nutrition in surgical patients. The Veterans Affairs Total Parenteral Nutrition Cooperative Study Group [see comments]. N Engl J Med 325:525-532, 1991 11. Buzby GP, Mullen JL, Matthews DC, et a1 Prognostic nutritional index in gastrointestinal surgery. Am J Surg 139:160-167, 1980 12. Christie PM, Hill GL: Effect of intravenous nutrition on nutrition and function in acute attacks of inflammatory bowel disease. Gastroenterology 99:730-736, 1990 13. Crohn BB, Ginsburg L, Oppenheimer GD: Regional ileitis: A pathologic and clinical entity. JAMA 993323-1329, 1932 14. Dempsey DT, Mullen JL, Buzby GP: The link between nutritional status and clinical outcome: Can nutritional intervention modify it? Am J Clin Nutr 47352-356,1988 15. Dickinson RJ, Ashton MG, Axon AT, et al: Controlled trial of intravenous hyperalimentation and total bowel rest as an adjunct to the routine therapy of acute colitis. Gastroenterology 791199-1204, 1980 16. Driscoll RH Jr, Rosenberg M: Total parenteral nutrition in inflammatory bowel disease. Med Clin North Am 62:185-201, 1978 17. Ferguson A, Glen M, Ghosh S: Crohn’s disease: Nutrition and nutritional therapy. Baillieres Clin Gastroenterol 12:93-114, 1998 18. Fernandez-Banares F, Cabre E, Esteve-Comas M, et al: How effective is enteral nutrition in inducing clinical remission in active Crohn’s disease? A meta-analysis of the randomized clinical trials. JPEN J Parenter Enteral Nutr 19:356-364, 1995 19. Fernandez-Banares F, Cabre E, Gonzalez-Huix F, et al: Enteral nutrition as primary therapy in Crohn’s disease. Gut 35(suppl):55-59, 1994 20. Fleming CR Enteral and parenteral nutrition. In Peppercorn MA (ed): Therapy of Inflammatory Bowel Disease. New York, Marcel Dekker, 1990, pp 145-157 21. Galland L: Magnesium and inflammatory bowel disease. Magnesium 778-83, 1988 22. Gee MI, Grace MGA, Wensel RH, et al: Protein-energy malnutrition in gastroenterology patients: Increased risk in Crohn’s disease. J Am Diet Assoc 85:1466-1474, 1985 23. Greenberg GR, Fleming CR, Jeejeebhoy KN, et a1 Controlled trial of bowel rest and nutritional support in the management of Crohn’s disease. Gut 29:1309-1315, 1988 24. Griffiths AM, Ohlsson A, Sherman PM, et al: Meta-analysis of enteral nutrition as a primary treatment of active Crohn’s disease. Gastroenterology 108:1056-1067, 1995 25. Harries AD, Jones LA, Danis V, et al: Controlled trial of supplemented oral nutrition in Crohn’s disease. Lancet 1:887-890, 1983 26. Harries AD, Heatley RV: Nutritional disturbances in Crohn’s disease. Postgrad Med J 59:690-697, 1983 27. Harries AD, Jones LA, Heatley RV, et al: Malnutrition in inflammatory bowel disease: An anthropometric study. Human Nutrition-Clinical Nutrition 36:307-313, 1982 28. Heetderks-Cox JE: The comprehensive nutritional assessment. In Shikora SA, Blackbum GL (eds): Nutrition Support: Theory and Therapeutics. New York, Chapman & Hall, 1997, DD 3&53 29. Hickman ~ MMiller , RA, Rombeau JL, et al: Serum albumin and body weight as predictors of postoperative course in colorectal cancer. JPEN J Parenter Enteral Nutr 4314-316, 1980 30. Higashiguchi T, et al: Effect of glutamine on protein synthesis in isolated intestinal epithelial cells. JPEN J Parenter Enteral Nutr 17307-314, 1993
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31. Hill G L Massive enterectomy: Indications and management. World J Surg 9:833-841, 1985 32. Hill GL: Operative strategy in the treatment of enterocutaneous fistulas. World J Surg 7495-501, 1983 33. Hill GL, ‘Blackett RL, Pickford I, et al: A survey of protein nutrition in patients with inflammatory bowel disease: A rational basis for nutritional therapy. Br J Surg 64:894-896, 1977 34. Hill GL, Blackett RL, Pickford I, et al: Malnutrition in surgical patients: An unrecognised problem. Lancet k689-692, 1977 35. Imes S, Pinchbeck 8, Thomson AB: Diet counseling improves the clinical course of patients with Crohn’s disease. Digestion 397-19, 1988 36. Jeejeebhoy KN: Nutritional aspects of inflammatory bowel disease. In Kirsner JB, Shorter RG (eds): Inflammatory Bowel Disease, ed 4. Baltimore, Williams & Wilkins, 1995, pp 734-749 37. Karulf RE: Patients with inflammatory bowel disease. In Shikora SA, Blackbum GL (eds): Nutrition Support: Theory and Therapeutics. New York, Chapman & Hall, 1997, pp 410-421 38. Kelly DG, Fleming CR Nutritional considerations in inflammatory bowel diseases. Gastroenterol Clin North Am 24:597-611,1995 39. Kelts DG, Grand RJ, Shen G, et al: Nutritional basis of growth failure in children and adolescents with Crohn’s disease. Gastroenterology 76:72&727, 1979 40. Lanfranchi GA, Brignola C, Campieri M, et a1 Assessment of nutritional status in Crohn’s disease in remission or low activity. Hepatogastroenterology 31:129-132, 1984 41. Lasher BA: Clinical features, laboratory findings, and course of Crohn’s disease. In Kirsner JB, Shorter RG (eds): Inflammatory Bowel Disease, ed 4. Baltimore, Williams & Wilkins, 1995, pp 344-354 42. Lindor KD, Fleming CR, Ilstrup DM: Preoperative nutritional status and other factors that influence surzcal outcome in patients with Crohn’s disease. Mayo Clin Proc 60:393-396,1985 43. Luck MS, Bass D: Effect of epidermal growth factor in an experimental model of colitis in the rat. J Pharmacol Exp Ther 204:984, 1993 44. Meakins JL, Rietsch JB, Bubenick 0, et a1 Delayed hypersensitivity: indicator of acquired failure of host defenses in sepsis and trauma. Ann Surg 186:241-250, 1977 45. Morin CL, Roulet M, Roy CC, et a1 Continuous elemental enteral alimentation in children with Crohn’s disease and growth failure. Gastroenterology 79:1205-1210,1980 46. Mullen JL, Buzby GP, Waldman MT, et al: Prediction of operative morbidity and mortality by preoperative nutritional assessment. Surg Forum 30:8&82, 1979 47. Mullen JL, Gertner MH, Buzby GP, et al: Implications of malnutrition in the surgical patient. Arch Surg 114121-125, 1979 48. Muller JM, Keller HW, Erasmi H, et a1 Total parenteral nutrition as the sole therapy in Crohn’s disease: A prospective study. Br J Surg 70:40-43,1983 49. Petschow BW, Carter DL, Hutton G D Influence of orally administered epidermal growth factor on normal and damaged intestinal mucosa in rats. J Pediatr Gastroenterol Nutr 1749-58, 1993 50. Pettit SH, Irving M H The operative management of fistulous Crohn’s disease. Surg Gynecol Obstet 167223-228, 1988 51. Polk DB, Hattner JT, Kerner JAJ: Improved growth and disease activity after intermittent administration of a defined formula in children with Crohn’s disease. JPEN J Parenter Enteral Nutr 16:499-504, 1992 52. Procaccino F, Reinshagen M, Hoffman P: Protective effects of epidermal growth factor in an experimental model of colitis in rats. Gastroenterology 10712-17, 1994 Wilkens DB, et al: Incidence and mortality of hypoalbu53. Reinhardt GF, Myscofski JW, minemic patients in hospitalized veterans. JPEN J Parenter Enteral Nutr 4:357-359,1980 54. Royall D, et a1 Comparison of amino acid v peptide based enteral diets in active Crohn’s disease: Clinical and nutritional outcome. Gut 35:783-787, 1994 55. Royall D, Greenberg GR, Allard JP, et a1 Total enteral nutrition support improves body composition of patients with active Crohn’s disease [see comments]. JPEN J Parenter Enteral Nutr 19:95-99, 1995
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56. Sax HC, Souba WW: Enteral and parenteral feedings: Guidelines and recommendations. Med Clin North Am 77868-880,1993 57. Seltzer MH, Fletcher HS, Slocum BA, et a1 Instant nutritional assessment in the intensive care unit. JPEN J Parenter Enteral Nutr 5:70-72, 1981 58. Souba WW, Smith RJ, Wilmore DW Glutamine metabolism by the intestinal tract. JPEN J Parenter Enteral Nutr 9:60&617, 1985 59. Spector MH, Traylor J, Young EA, et a1 Stimulation of mucosal growth by gastric and ileal infusion of single amino acids in parenterally nourished rats. Digestion 21:3MO, 1981 60. Stokes MA: Crohn’s disease and nutrition. Br J Surg 79:391-394, 1992 61. Stokes MA: The short gut. Current Practice of Surgery 2139-145, 1990 62. Van Buren CT, Kulkrni AD, Rudolph FB: The role of nucleosides in adult nutrition. J Nutr 124(~~pp1):160-164, 1994 63. Von Meyenfeldt MF, Meijeriuk WJHJ, Rouflart MMJ: Perioperative nutritional support: A randomized trial. Clin Nutr 11:180-186, 1992 64. Vovy R, Stringel G, Thomas R Effect of dietary nucleosides on growth and maturation of the developing gut in the rat. J Pediatr Gastroenterol Nutr 10:497-503, 1990 65. Wilmore DW, Dudrick SJ, Daly JM, et a1 The role of nutrition in the adaptation of the small intestine after massive resection. Surg Gynecol Obstet 132:673-680, 1971 66. Wilschanski M, Shermin P, Pencharz P, et al: Supplementary enteral nutrition maintains remission in paediatric Crohn’s disease. Gut 38543-548, 1996 67. Winitz M, Adding RF, Seedman DA, et al: Studies in metabolic nutrition employing chemically defined diets: 11. Effects on gut microflora population. Am J Clin Nutr 23:546549, 1970 68. Young GA, Hill G L Assessment of protein-calorie malnutrition in surgical patients from plasma proteins and anthropometric measurements. Am J Clin Nutr 31:429435, 1978
Address reprint requests to Howard K. Song, MD Silverstein Pavilion, 4th Floor Department of Surgery Hospital of the University of Pennsylvania 3400 Spruce Street Philadelphia, PA 19104
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NUTRITIONAL SUPPORT FOR CROHN’S DISEASE Howard K. Song, MD, and Gordon P. Buzby, MD
Disordered nutrition has been associated with Crohn’s disease since the initial description of the disease in 1932.13Crohn recognized weight loss, which occurs in as many as 76% of patients, as a predominant feature of the disease, and subsequent studies have demonstrated that specific deficiencies in amino acids and micronutrients also are comm ~ nDespite . ~ ~ the high frequency of malnutrition among patients with Crohn’s disease, monitoring of the nutritional status of these patients often is insufficient.2*l7 Systematic nutritional assessment should be a routine part of the management of all patients with Crohn‘s disease, to guide nutritional intervention as supportive therapy. Some trials have focused on the potential usefulness of nutritional intervention as a primary anti-inflammatory therapy for patients with Crohn’s disease. MALNUTRITION IN CROHN’S DISEASE
Origins Malnutrition, in general, may result from several basic mechanisms: inadequate intake, malabsorption, increased losses, increased requirements, and drug-nutrient interactions. The cause of malnutrition in Crohn’s disease is usually multifactorial, and factors representing each of these basic mechanisms contribute to the high prevalence of nutritional deficiency among these patients.16,26 Common factors leading to malnu-
From the Department of Surgery, University of Pennsylvania Medical Center (HKS); and Clinical Nutrition Support Services, Hospital of the University of Pennsylvania (GPB), Philadelphia, Pennsylvania
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Table 1. CAUSES OF MALNUTRITION IN PATIENTS WITH CROHN’S DISEASE Basic Mechanism
Inadequate intake Malabsorption
Increased losses Increased requirements Drug-nutrient interactions
In Crohn’s Disease
Anorexia, fear of abdominal pain after eating Loss of absorptive surface from disease or surgery; mucosal cell disease; stagnant-loop syndrome from strictures, fistulas, or surgical blind loops; lymphangiectasia; rapid gastrointestinal transit Exudation from mucosa, fistulas, interrupted enterohepatic circulation Active inflammation, sepsis Sulfasalazine, corticosteroids, antibiotics
Data from references 16,26,38, and 60
trition in patients with Crohn’s disease are summarized in Table 1. Patients with Crohn’s disease commonly have anorexia or limit their food intake because of abdominal pain or diarrhea associated with eating. Malabsorption of nutrients can result from loss of absorptive surface area secondary to mucosal involvement with disease, shortbowel syndrome, terminal ileal resection, stagnant loop syndrome, lymphangiectasia, and rapid gastrointestinal transit. Exudation associated with inflammation, fistulas, and interrupted enterohepatic circulation can lead to protein, water, electrolyte, and fatty-acid losses. Nutritional requirements are increased in patients with active inflammation, infection, sepsis, and accelerated mucosal cell turnover. Several drugs commonly used in the treatment of Crohn’s disease have important effects on nutrient absorption and use. Sulfasalazine decreases folate absorption; corticosteroids alter protein metabolism, inhibit calcium absorption, and induce magnesemia; antibiotics modify gut floras and thereby can affect vitamin K metabolism. Specific Deficiencies
The specific nutritional deficiencies in patients with Crohn’s disease are detailed in Table 2. Weight loss has been regarded as a predominant feature of Crohn’s disease since its first description and occurs in as many as 76% of patients in some seriesz0Even in a subset of patients without active disease, as many as 20% may be more than 10% below ideal In pediatric patients, growth retardation often precedes clinical onset of Crohn’s disease. Approximately one third of children with active disease have delayed linear growth and delayed onset of Although absorption of carbohydrates usually is preserved in patients with Crohn’s disease, protein and fat absorption are decreased, which can lead to specific nutrient Amino-acid deficiencies contribute to hypoalbuminemia and hypoproteinemia. Intestinal protein loss, reduced hepatic protein synthesis, increased catabolism, and anorexia also promote this condition, making serum albumin levels more
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Table 2. PREVALENCE OF NUTRITIONAL DEFICIENCIES AMONG PATIENTS WITH CROHN'S DISEASE Deficiency
Prevalence (%)
Weight loss Growth retardation Hypoalbuminemia Anemia Iron Folate Vitamin Blz Calcium Magnesium Potassium zinc
65-76 40 25-80 60-80 39 54 48 13
14-88 6-20 40-50
Data from references 20-21 and 38
a marker of disease activity than nutritional status.60Impaired fat absorption in some patients, exacerbated by interrupted enterohepatic circulation, may contribute to decreased absorption and deficiencies of calcium, magnesium, and zinc.31 Anemia in patients with Crohn's disease is common, and its cause may be m~ltifactorial.'~ Iron, folate, and vitamin B,, deficiencies are all common. Also, patients with active disease may have anemia related to chronic inflammation even in the absence of a specific nutritional deficit. Patients with Crohn's disease also may have deficiencies in vitamins C, D, K, and trace metals, such as selenium. Deficiencies of these nutrients usually are not clinically overt.6O Nutritional Assessment of Patients with Crohn's Disease
Timely recognition of malnutrition allows for early nutritional intervention and correction of deficits, which is important in the care of surgical patients who have a high prevalence of unrecognized malnutrit i ~ nAlso, . ~ presurgical nutritional support for severe malnutrition reduces postsurgical complications related to malnutrition.10,63 The nutritional assessment of all these patients begins with detailed history taking and a physical examination. Specific areas to address in this patient population include current disease activity; previous surgeries; and symptoms related to Crohn's disease, such as abdominal pain, enteric fistulas, bowel obstruction, diarrhea, steatorrhea, hematochezia, and fever, which may affect nutrient intake, losses, and metabolism. Changes in appetite, food intake, and weight should be documented routinely. Various methods are available to assess the adequacy of dietary intake, including 24-hour recall of intake and prospectively recorded food records and calorie counts.28Medications should be reviewed for drug-nutrient interactions. These patients should be exam-
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ined for physical signs of vitamin and trace-element deficiencies and muscle wasting more typical of protein-energy malnutrition. Children with Crohn's disease commonly have delays in growth and development, making monitoring of these processes important. Ideally, height, weight, sexual staging, and bone age are monitored regularly during the course of care.I7 Despite this, some studies have found severe underrecording of growth parameters by physicians during the routine followup of children with Crohn's disease.2,l7 Laboratory studies are a useful adjunct in the nutritional assessment of patients with Crohn's disease. A complete blood count is useful given the high prevalence of anemia among these patients. Iron, folate, and vitamin BIZmeasurements are necessary to determine the specific nutrient deficiency responsible for anemia after it is recognized. Lymphopenia related to protein deficiency also may be detected on screening complete blood Measurement of serum electrolytes also is important given the high prevalence of electrolyte deficiencies, particularly among patients presenting with surgical complications of Crohn's disease, such as bowel obstruction or enterocutaneous fistulas. Although the levels of serum proteins, such as albumin, prealbumin, and transferrin commonly are decreased, the cause of hypoproteinemia in patients with Crohn's disease is usually multifactorial and may not be related only to specific amino-acid deficiencies. Dissatisfaction with biochemical techniques has led to the use of anthropometric data for the nutritional assessment of at-risk patients, including patients with Crohn's disease." 27, 33, 40 Skinfold and limbcircumference measurements are performed easily, and when these data are related to the amount of adipose tissue and lean body mass using standard tables, they better reflect the nonspecific malnourishment typically encountered in patients with Crohn's disease.60Finally, several multivariant analyses of nutritional parameters have been performed to develop formulas that relate the risk for postsurgical complications with presurgical nutritional status. One such formula is the prognostic nutrition index, which is calculated as follows: PNI = 158 - 16.6 (Alb) - 0.78 (TSF) - 0.2 (TFN) - 5.8 (DH) where PNI is the prognostic nutrition index, Alb is serum albumin (g/dL), TSF is triceps skinfold (mm), TFN is serum transferrin (mg/dL), and DH is delayed cutaneous hypersensitivity graded from 0 to 2.11Although the prognostic nutrition index has not been validated prospectively for the presurgical evaluation of patients with Crohn's disease per se, application of this nutritional assessment prospectively to 100 nonemergent general surgical patients was highly predictive of postsurgical complications." NUTRITION AS SUPPORTIVE THERAPY FOR CROHN'S DISEASE
Nutritional therapy has a potential role in the treatment of Crohn's disease, in several settings, as a supportive and primary therapy. Nutri-
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tional therapy is indicated as a supportive measure to (1) improve the nutritional status of malnourished patients; (2) meet the nutritional requirements of patients being treated for active Crohn’s disease medically and with bowel rest; (3) perioperatively reduce protein loss and morbidity related to surgery; and, (4) manage complications of surgical therapy for Crohn‘s disease, such as enterocutaneous fistulas and shortbowel syndrome. Improving Nutritional Status
Patient education and dietary manipulation are early supportive measures that may be used to improve the nutritional status of malnourished ~atients.3~ Properly educated patients are better able to monitor dietary intake and continuously assess their own risk for malnutrition. Reduction of dietary bulk and fat may decrease symptoms related to Crohn’s disease, such as abdominal pain, diarrhea, and steatorrhea, that adversely affect patients’ nutritional status by leading to anorexia and malabsorption.’ Restriction of dietary fat necessitates supplementation with other foods to maintain adequate caloric intake. Carbohydrates are a useful source of calories in these patients because they are readily absorbed. High dietary protein intake also is important to maintain weight, replace protein losses, and preserve skeletal and respiratory muscle function. Multivitamin supplements also may be necessary to prevent or replace micronutrient deficiencies. Nutritional therapy may have an important role in the supportive treatment of children with Crohn’s disease who commonly suffer from delayed linear growth and development. Multiple studies have demonstrated that growth and development resume in these patients when nutritional therapy is instituted before epiphyseal closure.39,45 Nutritional supplementation may be economically and conveniently administered by liquid formulations containing a carbohydrate source and hydrosylated proteins or free amino acids. Elemental formulas may be specifically indicated for patients with impaired absorption related to small-bowel involvement with disease, short-bowel syndrome, and diarrhea. Although more easily absorbed, elemental formulas are unpalatable and typically are administered through fine-bore nasogastric feeding tubes, which are generally well tolerated. Some form of oral or enteral feeding is usually suitable for most patients with Crohn’s disease who require supplementation to improve their nutritional status. Adjuvant Therapy for Active Crohn’s Disease
The optimal primary treatment of Crohn‘s disease, and the role that bowel rest may have in allowing more rapid resolution of acute attacks, are debatable. Although bowel rest has been advocated for the primary treatment of acute Crohn’s disease, multiple studies have shown no
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primary therapeutic effect or poorly sustained results in patients treated 48 On primarily with bowel rest and total parenteral nutrition (TPN).36, the other hand, investigators generally agree that a synergistic effect occurs when nutritional supplementation is given to patients receiving steroid therapy for active Crohn's disease. TI" has been found to prevent protein loss and preserve skeletal and respiratory muscle function in such patients.12 Administration of total enteral nutrition to malnourished patients being treated for active Crohn's disease has been found to allow modest weight gain.55 Nutritional Therapy During the Perioperative Period
Surgical patients are predisposed to malnutrition, which also is true of patients with Crohn's disease. As many as 50% of surgical patients 34 Further underscorhave malnutrition that is commonly unre~ognized.~, ing the importance of nutritional assessment and support in the care of surgical patients, several studies have demonstrated a close association between malnutrition and postsurgical morbidity.*The broad availability of TPN and increased awareness of perioperative morbidity secondary to nutrition-related complications has led to the widespread application of perioperative TPN with the intent of reducing postsurgical complications. This approach has been validated by several large, prospective, randomized studies that have demonstrated that severely malnourished general surgical patients receiving a 7-day to 10-day course of TI" presurgically benefit from a reduction in major, noninfectious complications.lO,63 This benefit was not demonstrated in well-nourished or only moderately malnourished patients. Series studying perioperative TPN specifically for the care of patients with inflammatory bowel disease have been somewhat less persuasive. These smaller studies have failed to demonstrate a reduction in surgical morbidity in patients with active Crohn's disease treated presurgically with TPN. A prospective study of 19 clinically malnourished patients who had acute exacerbations of Crohn's disease showed that short courses of TI" in these patients prevent protein loss and result in significant improvements in skeletal and respiratory muscle function.12 Also, patients with Crohn's disease who have low serum protein levels in one study were found to have an approximately fivefold increase in surgical complication rate compared with patients with normal serum protein levels.42These findings support the concept that supportive nutritional therapy may have efficacy in the reduction of surgical morbidity in malnourished patients with Crohn's disease. In the absence of large, prospective clinical trials that specifically address this issue, presurgical administration of short courses of TPN to severely malnourished patients for whom surgery may be safely delayed is a rational use of supportive nutritional therapy. Also, if surgery must be *References6, 14, 29, 44, 46-47, 53, 57, and 68.
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delayed to address other issues (e.g., preparing the bowel, decreasing fistula output, and improving peristomal inflammation), then nutritional support should be provided to prevent further deterioration during mandatory presurgical fasting. Nutritional Therapy for Enterocutaneous Fistulas
Enterocutaneous fistulas in patients with Crohn‘s disease arise in two settings.32,50 Type 1 fistulas arise from an area of bowel affected by active Crohn’s disease. Type 2 fistulas arise from a site of anastomosis after surgical resection. Type 1 fistulas rarely heal with conservative measures and typically mandate surgery. Type 2 fistulas, on the other 50 This hand, commonly heal with bowel rest and nutritional support typically is given in the form of TPN, but elemental enteral nutrition may be used for distal fistulas because these diets are almost entirely absorbed by the first 100 cm of small intestine. Nutritional Therapy for Short-Bowel Syndrome
Short-bowel syndrome is the clinical syndrome of diarrhea, fluid and electrolyte disturbances, and malabsorption that follows extensive small-bowel resection.* Despite the current emphasis on conservative surgery for Crohn’s disease, surgery for this disorder is the most common cause of short-bowel syndrome in adult populations.61Short-bowel syndrome is of concern after extensive small-bowel resection for Crohn’s disease because such resections often lead to loss of the ileocecal valve. Many patients with an intact ileocecal valve and pylorus can resume nearly normal gut function after the bowel adapts by assuming greater absorptive capacity. In such patients, segments of jejunum as short as In 30.5 cm have been reported to eventually support enteral patients lacking an ileocecal valve, however, approximately 100 cm of bowel may be necessary to maintain adequate enteral f u n ~ t i o n . ~ When massive or serial resections leave a patient with less than this amount, inadequate intestinal absorptive area and short transit time lead to incomplete digestion and absorption of carbohydrates, fats, and proteins. Loss of the ileum causes malabsorption of vitamin BIZ and interruption of the enterohepatic circulation, which exacerbates fat malabsorption and steatorrhea. Fat malabsorption and steatorrhea lead to wasting of the fat-soluble vitamins A, D, E, and K, and increased excretion of calcium and magnesium, which results in severe vitamin and electrolyte deficiencies. Patients with short-bowel syndrome require replacement of fluid and electrolytes, provision of adequate calories, and supplementation of inadequately absorbed nutrients and minerals. Short-bowel syndrome was one of the first indications for which TPN was originally developed, and for these patients, TPN is life~aving.~~ TPN should be administered
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beginning immediately after surgery to prevent protein losses related to the catabolic effects of surgery and to nutritionally support the patient during healing and bowel adaptation” After the immediate postsurgical period, assessment of the patient’s enteral function is begun. Adaptation by the bowel occurs over months or years, during which the patient’s TPN regimen is tailored to replace specific nutritional constituents not absorbed from the patient’s oral feedings. Oral intake usually is begun in the form of an isotonic elemental formula to maximize absorption and minimize diarrhea and steatorrhea related to malabsorption. These symptoms may be controlled further with antimotility agents, such as loperamide. Surviving patients with marginal bowel function must maintain a delicate balance between their disorder and the nutritional regimen necessary to sustain them. Illnesses may increase metabolic requirements, and recurrent Crohn‘s disease may diminish bowel function, affecting patients’ requirements for supportive nutritional therapy. These patients should be followed up closely so that specific nutritional and metabolic derangements may be corrected as they occur. NUTRITION AS PRIMARY THERAPY FOR CROHN’S DISEASE
Intraluminal gut antigens, derived from dietary intake and bowel flora, have been widely proposed to have a role in the pathogenesis of Crohn’s disease.67This suspicion led to nutritional interventions that may reduce antigenic load delivered to the intestinal mucosa and thereby act as a primary anti-inflammatory the rap^.^ The initial enthusiasm for the widespread use of nutrition as a primary therapy for Crohn‘s disease has waned with the advent of carefully controlled studies demonstrating the superiority of corticosteroids in the treatment of active Crohn‘s disease, but indications for the selective use of primary nutritional therapy for Crohn’s disease are emerging as the association between patients’ nutritional status and their level of disease activity has become better appreciated. Parenteral Nutrition for Acute Crohn’s Disease
TPN has been proposed to act as a primary therapy for active Crohn’s disease by “resting” the bowel from absorptive function and allowing healing of affected areas.l5 This rationale has been challenged in a prospective multicenter trial and is no longer thought to be ~ a l i d . 2 ~ When TPN was used as sole therapy for Crohn‘s disease in one study, patients had a 36% resection rate after one year and a fourfold increase in relapse rate.@Therefore, TPN does not have a primary therapeutic role in the treatment of active Crohn’s disease. Attention has been focused on the potential use of enteral nutrition in this setting.
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Enteral Nutrition for Acute Crohn’s Disease Enteral nutrition has several effects that are of potential benefit in the treatment of Crohn‘s disease. Elemental enteral diets have been proposed to reduce the antigenic exposure of the intestinal mucosa by altering the bowel flora and by replacing the complex protein antigens present in normal foodstuffs with free amino acids or ~ligopeptides.~~ Another potential advantage of enteral nutrition over parenteral nutrition is the direct nourishment of the intestinal mucosa by the feeding solution.=,59 This is thought to lead to improved mucosal integrity and reduced protein losses. Provision of glutamine holds great promise in this regard because of its trophic effects on the small intestine and 30, 58 Epidermal proposed beneficial effects on gut immune fun~tion.~, growth factor also induces intestinal growth and repair and exerts a 49, 52 Nucleotides have protective effect in animal models of been shown to stimulate intestinal growth and have been proposed to modulate intestinal repair after injury.62,64 More studies are necessary to determine the role of these and other trophic factors in the management of patients with Crohn‘s disease. Conventional enteral nutrition for the treatment of active Crohn’s disease has been evaluated in several prospective, randomized, controlled trials.l8*24 Although efficacy of enteral nutrition has been shown, relapse of disease activity has been seen in many patients within several months of stopping the enteral nutritional therapy.19Also, none of these studies have demonstrated an advantage of elemental or whole-proteinbased diets over steroid therapy in the treatment of active Crohn’s disease.18A meta-analysis of these studies supports the overall conclusion that steroid therapy is more effective than enteral nutrition in the management of active Crohn’s disease.24Despite this, enteral nutrition is a reasonable secondary therapeutic option for patients with active Crohn’s disease who are intolerant or resistant to steroids; as many as 40% of these patients achieve a therapeutic e f f e ~ t . ~
Enteral Nutrition for the Maintenance of Clinical Remission An emerging indication for enteral nutrition in the management of patients with Crohn’s disease is in the maintenance of disease remission. Several smaller studies have identified a beneficial effect of supplementary enteral nutrition without restriction of normal diet in patients treated between acute attack^.^, 25, 51, 66 Supplementary enteral nutrition provided orally or through nasogastric feeding tubes nocturnally has been associated with prolongation of remission and, in adolescent and pediatric patients, improved linear growth. The mechanism by which enteral nutrition mediates reduction in intestinal inflammation is unclear. Bowel rest does not have a role because enteral nutrition was provided as a supplement without restric-
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tion of normal oral intake. Rather, clinical remission has been correlated with improvements in nutritional status, suggesting that the anti-inflammatory effects of enteral nutrition in this setting are primarily nutritional.%Whether these effects are dependent on improving the overall nutritional state or on the provision of a specific micronutrient, such as glutamine, is unknown. Irrespective of the mechanism, results of early clinical trials using this approach have been encouraging and warrant larger, prospectively performed studies in the future. In the interim, selective use of supplementary enteral nutrition for the maintenance of remission of Crohn’s disease seems reasonable, particularly in children, in whom improvements in patients’ growth and development would be expected to further enhance their well-being.
SUMMARY
Nutritional considerations are intimately associated with Crohn’s disease. Food antigens and dietary factors have been postulated to have a role in its pathogenesis, and the disease leads to decreased absorptive capacity of the gut. Malnutrition is a common manifestation of Crohn’s disease, necessitating close monitoring of patients and rapid nutritional intervention to correct deficiencies. The indications for supportive nutritional therapy are well defined and include measures to improve patients’ nutritional status and growth and development; decrease perioperative complications; and manage complications of Crohn‘s disease, including enterocutaneous fistulas and short-bowel syndrome. Nutritional therapy as a first-line treatment of Crohn‘s disease is controversial. Although enteral nutrition has been found to have efficacy in this setting, steroid therapy is the gold standard treatment of acute Crohn‘s disease, with enteral nutrition reserved for steroid-resistant or steroid-intolerant patients. An emerging use of supplementary enteral nutrition is in the maintenance of Crohn’s disease remission. Interestingly, this benefit seems to be associated with improvement in patients’ nutrition, suggesting a relationship between nutritional status and disease activity. Further insight into this field, including the potential of micronutrients to promote trophic, healing, and immunomodulatory effects on the gut, may lead to novel and efficacious treatments of this disease.
References 1. Alexander-Williams J, Haynes IG: Up-to-date management of small-bowel Crohn’s disease. Adv Surg 20245-264, 1987 2. Barton JR, Ferguson A Failure to record variables of growth and development in children with inflammatory bowel disease. BMJ 298:423439, 1989 3. Belli DC, Seidman E, Bonthillier L, et al: Chronic intermittent elemental diet improves growth failure in children with Crohn’s disease. Gastroenterology 94:603410,1988 4. Bergren CT: Indications for parenteral nutrition. In Shikora SA, Blackbum GL (eds):
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Nutrition Support: Theory and Therapeutics. New York, Chapman & Hall, 1997, pp 113-119 5. Bemstein CN, Shanahan F Critical appraisal of enteral nutrition as primary therapy in adults with Crohn’s disease [see comments]. Am J Gastroenterol91:2075-2079,1996 6. Bistrian BR, Blackbum GL, Hallowell E, et al: Protein status of general surgical patients. JAMA 230:858-860, 1974 7. Blackbum GL, Bistrian BR, Maini BS, et al: Nutritional and metabolic assessment of the hospitalized patient. JPEN J Parenter Enteral Nutr 1:ll-22, 1977 8. Block GE, Hurst R D Complications of the Surgical Treatment of Ulcerative Colitis and Crohn’s Disease. Baltimore, Williams & Wilkins, 1995 9. Burke DJ, Alverdy JC, Aoys E, et al: Glutamine-supplemented total parenteral nutrition improves gut immune function. Arch Surg 1241396-1399, 1989 10. Buzby GP, et al: Perioperative total parenteral nutrition in surgical patients. The Veterans Affairs Total Parenteral Nutrition Cooperative Study Group [see comments]. N Engl J Med 325:525-532, 1991 11. Buzby GP, Mullen JL, Matthews DC, et a1 Prognostic nutritional index in gastrointestinal surgery. Am J Surg 139:160-167, 1980 12. Christie PM, Hill GL: Effect of intravenous nutrition on nutrition and function in acute attacks of inflammatory bowel disease. Gastroenterology 99:730-736, 1990 13. Crohn BB, Ginsburg L, Oppenheimer GD: Regional ileitis: A pathologic and clinical entity. JAMA 993323-1329, 1932 14. Dempsey DT, Mullen JL, Buzby GP: The link between nutritional status and clinical outcome: Can nutritional intervention modify it? Am J Clin Nutr 47352-356,1988 15. Dickinson RJ, Ashton MG, Axon AT, et al: Controlled trial of intravenous hyperalimentation and total bowel rest as an adjunct to the routine therapy of acute colitis. Gastroenterology 791199-1204, 1980 16. Driscoll RH Jr, Rosenberg M: Total parenteral nutrition in inflammatory bowel disease. Med Clin North Am 62:185-201, 1978 17. Ferguson A, Glen M, Ghosh S: Crohn’s disease: Nutrition and nutritional therapy. Baillieres Clin Gastroenterol 12:93-114, 1998 18. Fernandez-Banares F, Cabre E, Esteve-Comas M, et al: How effective is enteral nutrition in inducing clinical remission in active Crohn’s disease? A meta-analysis of the randomized clinical trials. JPEN J Parenter Enteral Nutr 19:356-364, 1995 19. Fernandez-Banares F, Cabre E, Gonzalez-Huix F, et al: Enteral nutrition as primary therapy in Crohn’s disease. Gut 35(suppl):55-59, 1994 20. Fleming CR Enteral and parenteral nutrition. In Peppercorn MA (ed): Therapy of Inflammatory Bowel Disease. New York, Marcel Dekker, 1990, pp 145-157 21. Galland L: Magnesium and inflammatory bowel disease. Magnesium 778-83, 1988 22. Gee MI, Grace MGA, Wensel RH, et al: Protein-energy malnutrition in gastroenterology patients: Increased risk in Crohn’s disease. J Am Diet Assoc 85:1466-1474, 1985 23. Greenberg GR, Fleming CR, Jeejeebhoy KN, et a1 Controlled trial of bowel rest and nutritional support in the management of Crohn’s disease. Gut 29:1309-1315, 1988 24. Griffiths AM, Ohlsson A, Sherman PM, et al: Meta-analysis of enteral nutrition as a primary treatment of active Crohn’s disease. Gastroenterology 108:1056-1067, 1995 25. Harries AD, Jones LA, Danis V, et al: Controlled trial of supplemented oral nutrition in Crohn’s disease. Lancet 1:887-890, 1983 26. Harries AD, Heatley RV: Nutritional disturbances in Crohn’s disease. Postgrad Med J 59:690-697, 1983 27. Harries AD, Jones LA, Heatley RV, et al: Malnutrition in inflammatory bowel disease: An anthropometric study. Human Nutrition-Clinical Nutrition 36:307-313, 1982 28. Heetderks-Cox JE: The comprehensive nutritional assessment. In Shikora SA, Blackbum GL (eds): Nutrition Support: Theory and Therapeutics. New York, Chapman & Hall, 1997, DD 3&53 29. Hickman ~ MMiller , RA, Rombeau JL, et al: Serum albumin and body weight as predictors of postoperative course in colorectal cancer. JPEN J Parenter Enteral Nutr 4314-316, 1980 30. Higashiguchi T, et al: Effect of glutamine on protein synthesis in isolated intestinal epithelial cells. JPEN J Parenter Enteral Nutr 17307-314, 1993
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