The Journal of Nutrition Vol. 129 No. 1 January 1999, pp. 252S-255S

Wasting in Chronic Gastrointestinal Diseases¹

Rosemarie L. Fisher²

Yale University School of Medicine, New Haven, Connecticut 06520

	INTRODUCTION

Introduction References

The role of the gastrointestinal tract in the digestion and absorption of food products places it at the forefront of scenarios where wasting may occur. If the gastrointestinal tract is diseased or limited in length, it will be unable to fulfill its primary function. However, the problem of wasting in chronic gastrointestinal disease still requires definitiondoes wasting occur as a result of the chronic gastrointestinal disease; in association with, but not related to chronic gastrointestinal diseases; or as complications of the disease occur? In other words, are wasting and chronic gastrointestinal diseases true-true and related, or true-true and unrelated? In the majority of cases, chronic gastrointestinal disease is synonymous with wasting, at least until the disease is treated. In some instances, the wasting may come about as a result of medications or dietary limitations, but will resolve in most instances with therapy of the disease, change in diet recommendations or dietary supplementation. As opposed to other disease states, where the wasting may occur primarily because of inanition, the inability of the gastrointestinal tract to fulfill its role is the primary reason for wasting.

How then, as a gastroenterologist, does one approach the problem of wasting in chronic gastrointestinal diseases? The disease must first be defined and then the manner in which the disease process itself relates to, or causes the wasting must be determined. The ability to dissociate wasting from the disease process itself is very difficult. There is little in the literature to show that there continues to be wasting when diseases of the gastrointestinal tract are in remission or cured, and there continues to be adequate intake. The presence of other causes of decreased intake such as complications of medications for the disease (i.e., anorexia, nausea), or depression must still be considered, but are most likely not related directly to abnormalities in the gastrointestinal tract. There are however, certain exceptions to these ideas. One of the main contradictions to this basic premise is in patients presenting with AIDS and gastrointestinal involvement. Here, the wasting conditions which have been described in patients with AIDS will enter into the picture. The gastrointestinal disease may or may not accentuate that setting. Patients with gastrointestinal malignancy are another exception to the above statements. Here, the cachexia of malignancy may supervene over the ability of the GI tract to digest and absorb nutrients. Patients with systemic diseases, such as scleroderma, which might also involve the GI tract, may result in wasting, where treatment of the gastrointestinal involvement may be adequate to allow digestion and absorption of nutrients , but the systemic disease and the therapy of that disease might still cause wasting. Lastly, there may be patients where the therapy of the original disease may result in loss of ingestive, digestive and absorptive capability of the patient. An example of this may be an intestinal resection as a result of a retroperitoneal tumor or a radical neck dissection for a head and neck tumor.

	DEFINING THE DISEASES AND PROCESSES

In order to then look at why wasting occurs, one must define the alterations in the GI tract which will contribute to wasting. These can be classified under five main categories: obstruction to the delivery of nutrients; intestinal mucosal diseases leading to loss of mucosal absorptive surface; intraluminal maldigestion; pancreatic insufficiency; and hepatobiliary diseases. The patients with obstruction to the delivery of nutrients include those with malignancy of the head and neck, esophagus, or stomach; mucosal strictures; bypass of the GI tract, including fistulae which are due to malignancy or those that are surgically produced, such as those for weight reduction. Intestinal mucosal diseases constitute the largest proportion the scenarios when wasting occurs as a result of or in the presence of gastrointestinal diseases. The list is quite long and includes inflammatory bowel disease, primarily Crohn's disease, celiac disease, protein-losing enteropathy (which may also be secondary to a systemic process, such as congestive heart failure, or a retroperitoneal process), small intestinal diverticulosis, and short bowel syndrome secondary to surgical resection. The major non-pancreatic or hepatobiliary cause of intraluminal maldigestion include bacterial overgrowth and achlorhydria. The loss of pancreatic exocrine function secondary to chronic pancreatitis, pancreatic resection, cystic fibrosis or pancreatic duct obstruction secondary to stricture, trauma or cancer, leads to intraluminal maldigestion and subsequent malabsorption and wasting. Various hepatobiliary diseases result in the lack of intraluminal bile salts and maldigestion, but also results in decreased synthesis of both somatic and visceral proteins.

All of these disease presentations actually define the processes whereby wasting may occurinadequate intake of nutrients, maldigestion, malabsorption, malnutrition, increased losses of nutrients, increased requirements for nutrients (although this is not very common in chronic gastrointestinal diseases), the inability to assimilate nutrients, and lastly, and in many cases, most importantly, iatrogenic causes such as dietary restrictions, adverse drug events, and drug-food interactions.

	THERAPY AND EVALUATION OF WASTING IN GASTROINTESTINAL DISEASES

When the wasting process is then approached, several questions must be asked:

Some of these statements can be better defined and examined by looking at specific disease processes where wasting occurs.

	INFLAMMATORY BOWEL DISEASE

Malnutrition and wasting is common in inflammatory bowel disease (IBD), more so in Crohn's disease than in ulcerative colitis. The etiology of the wasting is multifactorial, and includes decreased oral intake, increased losses, increased requirements, malabsorption and maldigestion of nutrients and food-drug interactions and interference. Nutritional deficiencies in IBD are manifested in multiple ways, but are primarily seen by weight loss, hypoalbuminemia, negative nitrogen balance, anemia and various vitamin and mineral deficiencies. The frequency with which some of these deficiencies are seen in both Crohn's disease and ulcerative colitis is shown in Table 1. Clearly, with more of the small intestinal mucosa being involved in Crohn's disease, the greater the frequency and spectrum of nutritional deficiencies. Weight loss and body composition have been further studied in these diseases. It has been found that basal energy expenditure (BEE) in patients with Crohn's disease are similar to normal age and sex-matched controls, but that those patients with the lowest weight/ideal weight ratio had a greater energy expenditure (Chan 1986). It was questioned as to whether this was secondary to greater decreases in body fat in this group of patients. With this in mind, Royall et al. (1995), used a four-compartment model to study the body composition of 30 patients with active Crohn's disease, who were to be treated with 3 weeks of enteral nutrition, when compared to age and sex-matched controls without Crohn's disease. At entry, patients were 87% of ideal body weight. Body fat was the most significantly reduced component, at 70.3% of controls, giving further evidence to the fact that those patients with the lowest body fat have the greatest requirements. Patients who were treated with prednisone during the three weeks of feeding did not increase their protein stores when compared to those not receiving corticosteroids. Another study examined the total energy expenditure by dual-energy x-ray absorption in patients with Crohn's disease requiring enteral or parenteral nutrition support for 2 weeks (Stokes 1993). Drug interference or interaction as a cause of wasting or malnutrition is seen in the administration of sulfasalazine, where the active administration of folic acid is inhibited, hemolysis can occur, and nausea is a common side effect. Similarly the administration of corticosteroids can inhibit the absorption of calcium, and the administration of cholestyramine will inhibit fat absorption as well as the absorption of fat-soluble vitamins. In addition, the adverse effects of corticosteroids include muscle wasting. Because of either the presence of diseased bowel or the resection of diseased bowel, there is a decreased effective mucosal absorptive surface resulting in malnutrition, Bile acid deficiency states secondary to the loss of ileal mucosa and the ability to absorb bile acids, will result in steatorrhea. Areas of stricture, or blind loops secondary to fistula formation, or surgical bypass procedures, may result in bacterial overgrowth and vitamin deficiencies. In all of these instances, with the exception of steroid-induced wasting, the treatment of the primary disease, or supplementation of either modified diets or parenteral nutrition, or the supplementation of required or deficient nutrients will result in reversal of the malnutrition and wasting.

Inflammatory bowel disease in children will often present as growth failure or, in other words, wasting. Again, this occurs primarily in patients with Crohn's disease. Thirty to forty percent of patients with inflammatory bowel disease first present with their disease under the age of 21. Twenty to fifty percent of that group exhibit delays in linear growth and sexual maturation. In fact, growth failure may be the presentation of inflammatory bowel disease. Inadequate intake is the primary cause of the growth failure, although there may be secondary hormonal factors. As mentioned previously, the provision of required nutrients will result in the reversal of growth failure. This can be accomplished either by elemental diets, defined-formula diets or total parenteral nutrition (TPN). The growth failure can be reversed even in the presence of active Crohn's disease.

The therapy of wasting in patients with inflammatory bowel disease thus revolves around our ability to treat the disease itself, including modifying any drug therapy which may result in wasting. Adequate energy and protein intake needs to be ensured. In some patients the protein composition of the diet may need to be modified, such as the provision of small peptides or an elemental diet. Similarly, the administration of medium-chain triglycerides may result in adequate fat provisions. Lastly, one must ensure the provision of adequate vitamins and minerals, either enterally, or often times, parenterally.

	GUT FAILURE

The most severe form of wasting and malnutrition in patients with inflammatory bowel disease is seen when the extent of disease itself, or the resection of sufficient small bowel, results in gut failure. Additionally gut failure results from the resection of significant intestinal surface, so that there is simply not enough absorptive area remaining. At the present time, we have two methods of nutritional therapy for gut failure - total parenteral nutrition and small intestinal transplantation. Clearly the successful results of the latter will result in a return to normal function and the reversal of malnutrition and wasting. The experience with home parenteral nutrition in patients with Crohn's disease, as documented in the OLEY Foundation Registry (Howard 1995), shows us that wasting and malnutrition can be reversed by the provision of nutrients through home TPN. From 1985 to 1992, 10.8% of the 5481 patients on parenteral nutrition in the registry had Crohn's disease. Only 1.3% of the 4084 patients on home enteral nutrition had Crohn's disease. The mortality rate was 5% per year, and on average, patients were hospitalized for episodes of sepsis once every two years. More importantly, 70% of these patients had experienced complete rehabilitation at one year as measured by the ability to return to a functioning lifestyle which had been seen prior to gut failure, and 70% had resumed full oral nutrition at one year.

We need to answer several questions however, as we look at the therapy of gut failure, as this clinical setting will result in the ultimate case of wasting. We need to better define how best to replace needed nutrients -enterally versus parenterally. Are there certain nutrients, such as glutamine, short chain fatty acids, etc., which will be most beneficial in supporting gut function, or in stimulating the growth of intestinal mucosa? Studies of these `new` nutrients need to be well designed and controlled in order to differentiate the ability of these nutrients to reverse wasting and malnutrition when compared to standard therapies. Finally we need to define what endpoints are to be measured. Is the measurement of nutritional status or body composition an adequate measure, or should we be examining endpoints such as those examined by the OLEY Registry-partial or complete rehabilitation? In the OLEY registry, it became clear that survival rates were directly related to the underlying disease process, and not the ability to supply nutrients.

	PANCREATIC INSUFFICIENCY

The role of the pancreas in digestion, makes wasting a prominent feature in diseases of this organ. Patients with pancreatic insufficiency as a result of chronic pancreatitis, cystic fibrosis, pancreatic resection or other causes of pancreatic duct obstruction, including carcinoma will result in malabsorption. The causes of the wasting are multiple. Abdominal pain may limit the nutrient intake of patients. Reduced exocrine function will result in the maldigestion of fat, carbohydrate and protein. There must however be significant loss of exocrine function, as enzyme output must be decreased to 10% of normal prior to the development of malabsorption. Fat malabsorption will occur prior to the malabsorption of protein, and carbohydrate malabsorption is unlikely to be significant. Because of the presence of normal bile acid secretion and normal intestinal function in the vast majority of these patients, fluid absorption and fat-soluble vitamin absorption may not be dramatically impaired. While the presence of pancreatic enzymes is necessary to the absorption of vitamin B12, clinically overt deficiency of the vitamin is rare. If the etiology of the pancreatic insufficiency is chronic alcoholic pancreatitis, there may be confounding factors including chronic liver disease, and wasting related to alcohol itself.

Therapy in these patients is related to our ability to either supply exogenous pancreatic enzymes, or to supply modified oral nutrients which do not require the presence of pancreatic enzymes in order to be absorbed. These would include small peptide, free amino acids and medium-chain triglycerides. The provision of nutrients by the parenteral route may be necessary in cases where oral or enteral nutrition may not be possible. Lastly, if the etiology of the disease is related to alcohol, this must be stopped.

Studies and endpoints in this disease process should be similar to those in inflammatory bowel disease and gut failure. The ability of the patient to reinstitute the digestion and absorption of nutrients; the ability to gain weight and muscle mass; the decrease in stool fat and/or protein; the repletion of protein stores; and the repletion of fat-soluble vitamins can all be measured. However, we must be able to develop endpoints that are functional as well, including the ability to return to activities of daily living.

	CHRONIC LIVER DISEASE

The liver is essential to the maintenance of body protein, carbohydrate and fat. In liver failure, or severe disease, multiple metabolic effects, and thus wasting, occur, including derangements in protein metabolism and synthesis; decreased excretion of bile salts with subsequent malabsorption of fat and fat-soluble vitamins; and decreased storage of vitamins and trace elements. Again, the etiology of the wasting is varied depending on the disease process, and multifactorial-impaired dietary intake; intake of non-essential nutrients such as alcohol; maldigestion of nutrients secondary to decreased bile acid output; bacterial overgrowth with malabsorption; and inefficient metabolism of energy and protein by the damaged liver.

In chronic liver disease, metabolic needs are in general, not increased. However, patients may be metabolically unstable and unlikely to tolerate fasting or overfeeding. Glycogen stores may be diminished, and patients may demonstrate peripheral insulin resistance. In the presence of alcoholic liver disease, muscle wasting may be even more severe, secondary to the direct effects of alcohol on muscle. With cirrhosis, vitamin and mineral stores may be diminished.

The treatment of wasting in chronic liver disease consists first of improving nutrient intake. The use of anabolic steroids has been studied primarily in alcoholic liver disease, but has not gained wide acceptance as a standard therapy. Unfortunately, dietary restrictions may be necessary, including protein restriction if the patient has encephalopathy; and fluid and salt restriction. Fat-soluble and other vitamins and trace elements may need to be supplemented.

Where do we need to proceed to study wasting in chronic liver disease? Because of the role of the liver in protein metabolism and synthesis, the role of various structured protein supplements, or specific amino acids should be examined. The role of glutamine in patients with liver disease, and the possible adverse effects of glutamine will need to be carefully explored. The effects of liver transplantation on wasting clearly need to be studied. Whether wasting is completely reversed by the provision of a new organ, even in the presence of immunosuppressants should be examined. Evaluation of interventions and the development of endpoints becomes more of a problem in these patients because of the inherent inability of the liver when chronically diseased, to synthesize protein. Functional endpoints will be more important in these patients, although the standards for these measures may not be clearly defined.

In summary, wasting occurs frequently in chronic gastrointestinal disease states, and is in the vast majority of patients as a result of the disease process itself. The primary therapy of the wasting process thus depends on the therapy of the disease itself. The restitution of the gastrointestinal tract to its normal functioning state, with subsequent replacement of energy, protein, vitamin and mineral requirements, will in most cases result in the reversal of the wasting state. If this does not occur, the role of other intervention, such as drugs, and the role of the psychological state of the patient need to be examined. In instances where the gastrointestinal tract is not restorable, such as in the short bowel syndrome, the institution of total parenteral nutrition has been shown to be extremely effective. Future study designs and endpoints to evaluate wasting and its therapies in patients with gastrointestinal diseases, may be based on disease extent and activity, alterations in the loss of nutrients, and functional status.

	FOOTNOTES

	LITERATURE CITED

Introduction References

• Chan A.T.H., Fleming C. R., O'Fallon, W. M., Huizenga K. A. Estimated versus measured basal energy requirements in patients with Crohn's disease. Gastroenterology 1986; 91:75-78[Medline]
• Howard L., Ament M., Fleming C. R., Shike M., Steiger E. Current use and clinical outcome of home parenteral and enteral nutrition therapies in the United States. Gastroenterology 1995; 109:355-365[Medline]
• Royall D., Greenberg G. R., Allard J. P., Baker J. P., Jeejeebhoy K. N. Total enteral nutrition support improves body composition of patients with active Crohn's disease. J. Parenter. Enteral Nutr. 1995; 19:95-99[Abstract/Free Full Text]
• Stokes M. A., Hill G. L. Total energy expenditure in patients with Crohn's disease: Measurement by the combined body scan technique. J. Parenter. Enteral. Nutr. 1993; 17:3-7[Abstract/Free Full Text]

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