Date: 29 Mar 1995 17:56:23 From: zimitat@biosci.uq.edu.au Subject: Donald Kotler Lecture To: Recipients of conference From: zimitat@biosci.uq.edu.au (Craig Zimitat) Dear David, Thanks for the email copies of ATN, they are very much appreciated. Attached is a copy of a lecture that Dr Kotler delivered in Sydney Australia on March 27. Reprinted from HIV-EMIR with permission of Bristol-Myers. Impact of HIV Infection and AIDS upon Nutritional Status Donald P. Kotler, MD Malnutrition is a common complication of HIV-infection and is felt to play a significant and independent role in its morbidity and mortality. Progress in the field has been hampered by the large number of other priorities, the wide variety of potential pathogenic mechanisms, and the relative weaknesses of the tools for studying clinical nutrition outside of specialized research centers. However, the possibility of providing clinical benefit to patients using established and available modalities justifies the development and application of the techniques of nutritional monitoring and support. The aims of this presentation are to characterize the wasting processes that occur in HIV-infected individuals, to provide simple algorithms for diagnosis of the cause for wasting, and to resent studies illustrating the potential benefits of nutritional support. Previous studies have defined the characteristics of wasting in AIDS patients. Studies of body composition demonstrated depletion of body cell mass (protoplasmic mass) out of proportion to loss of weight as well as loss of body fat, a situation that differs from starvation and more closely resembles chronic sepsis. Intracellular water volumes were decreased, while relative extracellular water volumes were high, indicating over hydration. Overhydration may mask progressive weight loss and increase the difficulty in detecting wasting. The course of wasting illnesses was evaluated by examining the extent of body cell mass depletion as a function of the time before death. The results indicated a progressive depletion of body cell mass. The extent of depletion at death was about 50% of estimated premorbid values, corresponding to a body weight about one third below ideal. The results suggested that the timing of death from wasting in AIDS is related to the degree of body cell mass depletion rather than its specific cause. Progressive wasting is not an invariable consequences of AIDS. This was shown in a study of clinically stable patients, who were characterized by stable, moderate body cell mass depletion, normal caloric intake, mild-moderate malabsorption of sugars and fats, and hypometabolism. Other stages of the disease, and active systemic disease complications are associated with a hypermetabolism. Nutritional needs vary during the course of HIV infection as the complications and pathophysiologic processes promoting malnutrition each bear a different relationship to the level of immune function or dysfunction. The course of HIV infection can be subdivided into three basic stages, early, middle and late. The early stage includes seropositivity without clinical or immunological evidence of deficiency. Nutritional efforts at this point should be concentrated on education, to help assure a proper and balanced intake of macro and micronutrients. Aspects of food safety also should be taught, in preparation for a time when the GI tract may become vulnerable to pathogens. Misinformation can be corrected, and non-HIV related baseline deficits, which may include poverty or mental disease, identified and addressed. The middle phase of the disease is characterized by laboratory but not clinical evidence of immune deficiency. Patients often have non-specific symptoms and variable fatigue. Weight loss may occur but usually is not progressive. Experimental studies have demonstrated elevations in resting energy expenditure and evidence of a chronic inflammatory disorder may be found, including elevations of serum beta-2-microglobulin content, elevated urinary content of neopterin, and low levels of circulating alpha interferon. Mild hypertriglyceridemia may be found. Progressive wasting does not occur because the increase in resting energy expenditure appears to be compensated for by a decrease in voluntary energy expenditure. The precise cause for the metabolic abnormalities is unclear but may represent, at least in part, metabolic epiphenomena of anti-HIV immunity. Studies have shown that HIV production may be active in peripheral lymph nodes and mucous membranes during this phase of the disease. Some patients develop chronic diarrhoea with histologic evidence of mucosal inflammation, associated with evidence of HIV production. Routine stool examinations and cultures are negative, or if pathogens are found, effective treatment is not accompanied by prolonged symptomatic relief. The late stage of the disease includes patients with clinical evidence of immune deficiency, that is, patients with AIDS or who are undergoing active progression to AIDS. In these patients, malnutrition may occur and be severe and progressive. There is evidence that the extent of body mass depletion influences the timing of death in patients with wasting illnesses. However, body mass depletion is not a universal phenomenon in AIDS patients, implying that it occurs as a result of specific disease complications rather than from AIDS, per se. Diagnosis of the cause of malnutrition can be determined using an algorithmic approach. Food intake can be estimated by diet history or, more carefully, by formal calorie counts. If low, possible causes such as offending medications, local pathology, and focal or diffuse neurologic disease can be evaluated systematically. Since secondary anorexia may accompany malabsorptive or metabolic disorders, their evaluation also may be part of the workup. The presence of malabsorption, suggested by the complaints of diarrhoea, excess flatus, abdominal bloating, or other symptoms also can be evaluated using an algorithm. Noninvasive absorption studies can predict the presence of small intestinal versus colonic disease as the cause of diarrhoea. Nutrient malabsorption is occult or clinically mild in many patients. Vitamin B12 malabsorption may occur and lead to lower even subnormal serum concentrations, in the absence of other evidence of enteropathy. If small intestinal dysfunction is present and stool examinations are unrevealing, intestinal biopsy may be required to make the appropriate diagnosis. Etiologic diagnosis of malabsorption syndromes should be possible in more than two thirds of patients and includes such infections as cryptosporidiosis, microsporidiosis, Mycobacterium avium intracellulare, and chronic bacterial enteropathy. In the absence of such infections, mucosal architecture and the activities of mucosal enzymes may be normal. Thus, the intestine of an AIDS patient should be capable of absorbing sufficient nutrients to maintain nutritional status, in the absence of a specific complication. Metabolic derangements accompany systemic diseases and typically produce fatigue, tachycardia or fever. Some metabolic derangements, recently recognized to occur in HIV-infected individuals may not cause hypermetabolism. Muscle wasting due to loss or endogenous anabolic factors, such as testosterone, may occur in the absence of other disease complications and without detectable changes in nutrient intake or absorption. The question of providing nutritional support in AIDS is an important one, given the numbers of patients seen and the severity of the malnutrition. The importance of effective treatment of underlying infections was demonstrated during a longitudinal study of AIDS patients. The development of a serious complication (cytomegalovirus colitis) was invariably accompanied by progressive tissue depletion. On the other hand, may patients treated for this complication with an antiviral agent capable of suppressing cytomegalovirus repleted body mass, in the absence of nutritional support. Furthermore, other patients who had coexisting untreated infections, failed to replete body cell mass, even when nutritional support was administered along with the antiviral agent. Nutritional support frequently is indicated in patients with AIDS, who have received a variety of parenteral and enteral approaches. The efficacy of prolonged TPN was evaluated in 12 patients. In this study the response to TPN varied based upon the underlying clinical problem. Nutritional repletion was possible in patients whose clinical problem related to nutrient assimilation, such as a severe eating disorder or malabsorption. On the other hand, patients with disseminated systemic infections did not replete body cell mass in response to TPN, and increased body fat content instead. The ability of enteral nutritional reigmens to promote repletion also has been examined. The diet, given via a percutaneous endoscopic gastrostomy resulted in significant increases in body cell mass as well as serum protein concentrations. The repletion occurred despite the persistence of systemic infections in several patients. The nutritional improvement was associated with marked functional improvement, and all patients but one were able to leave the hospital. In addition, there was suggestive evidence of some improvement in immunity. The use of appetite stimulants has been reported. Megasterol acetate (Megacs, Bristol Myers) was shown to increase body weight in a multicenter, placebo-controlled trial. However, the large majority of weight gained was body fat. Trials are ongoing to test the ability of anabolic agents to promote body cell mass repletion. Positive nitrogen balance was demonstrated in short term studies. However, the sustained ability of anabolic agents to reverse the protein wasting effect of chronic inflammatory disease is unknown. The indications for nutritional support in an AIDS patient can be considered to be the same as in any other patient with a chronic disease i.e. significant body mass depletion, a persistent negative caloric balance, no overwhelming untreatable disease complications, and the potential for prolonged, comfortable survival if the wasting process is halted or reversed. Decisions regarding the mode and composition of the nutritional formula also should be based upon considerations that are used in other malnourished patients. Specifically, local impediments to food intake should be treated and efforts to stimulate spontaneous food intake should be undertaken. If intake is adequate, anabolic agents may be useful, though definitive studies need to be completed. If unsuccessful, nonvolitional feeding regimens can be utilized, applying the enteral route unless contraindicated by obstruction, severe injury or other factors. Parenteral nutrition may be given using supplemental formulae (PPN) for short periods of time in patients who are expected to resume normal intake, or total parenteral nutrition in the event of gut failure. It must be stressed that untreated, active infections are major impediments to nutritional repletion as a direct result of the associated metabolic derangements, so that nutritional support should be combined with an aggressive diagnostic and treatment plan. Continued progress in the elucidation and treatment of malnutrition in AID are needed to make the most effective use of this clinical tool in patients affected by immune deficiencies. The information obtained from treatment of AIDS patients also should be relevant to patients with other chronic, progressive, debilitating diseases. ----------------------- Craig ****************************************************************** _-_|\ Craig Zimitat / * Associate Lecturer \_.-._/ Department of Biochemistry v The University of Queensland, Australia 4072 Tel: +617 365 4608 * Fax: +617 365 4699 Editor: HIV Electronic Media Information Review Home: P.O. Box 999, Toowong, Brisbane, QLD, Australia 4066 260 Hawken Dr., St Lucia, QLD, Australia 4067. Tel: + 617 371 0082 ******************************************************************