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Distinguishing starvation from cachexia
Clin Geriatr Med 18 (2002) 883 – 891
Distinguishing starvation from cachexia David R. Thomas, MD, FACP, FAGS Division of Geriatric Medicine, Saint Louis Health Sciences Center, 1402 South Grand Boulevard M238, Saint Louis, MO 63140, USA
Starvation Simple starvation is caused by pure protein-energy deficiency. Starvation can be short-term (fasting) or long-term (chronic protein-energy undernutrition). Worldwide, starvation is most often caused by lack of food. In developed countries, undernutrition is most often related to medical causes. Obviously, failure to ingest adequate nutrients leads to undernutrition. Starvation occurring in the presence of adequate food can result from inability to swallow, a nonfunctioning gastrointestinal tract, or failure of appetite (anorexia). Strategies for involuntarily increasing the intake of nutrients include enteral or parenteral feeding. Increasing voluntary consumption of nutrients is more problematic. Appetite regulation is affected by illness, drugs, dementia, and mood disorders [1– 3]. Anorexia may be a physiologic response to aging, resulting from changes in the physiologic regulation of appetite and satiety [4]. Acute illness is characterized by a spontaneous decrease in food intake despite an increased need for energy and nutrients [5]. Although seemingly paradoxical, the voluntary suppression of food intake during illness is common to most species [6]. The reduction in food intake accompanying acute illness occurs both before and during hospitalization. In a prospective study of elderly people, 65% of the men and 69% of the women had an insufficient energy intake in the month before hospitalization. Undernutrition was present in 52.9% of men and 60.6% of women by the time of admission to the hospital [7]. This reduction in nutrient and energy intake at the beginning of an acute illness predisposes a patient to a risk for worsening undernutrition during hospitalization. Inadequate intake of nutrients continues during hospitalization. In 286 general medical patients, 27% became malnourished after hospital admission (defined as an post-admission reduction in mid-arm circumference of 3.6%). These patients were more likely to consume less than 40% of prescribed food and were more likely to have lower Mini-Mental Status Examination scores, functional impair-
E-mail address: [email protected] (D.R. Thomas). 0749-0690/02/$ – see front matter D 2002, Elsevier Science (USA). All rights reserved. PII: S 0 7 4 9 - 0 6 9 0 ( 0 2 ) 0 0 0 3 2 - 0
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D.R. Thomas / Clin Geriatr Med 18 (2002) 883–891
ment, lower total lymphocyte counts, and lower serum albumin levels than patients who were not malnourished [8]. Descriptive studies have shown that older adults with clinical or biochemical markers for undernutrition have poor outcomes. A reversal of illness-related anorexia or clinical benefit from hypercaloric feeding has been difficult to demonstrate, however. The observed reduction in food intake in ill older adults may be a physiologic adaptation to illness. The reduction in food intake is often equated with starvation. Starvation caused by inadequate availability of nutrients responds to hypercaloric feeding in both children and adults. If absorption is intact, provision of nutrients can be expected to reverse starvation. In starvation, repletion of serum albumin, cholesterol, improved immune function, and weight gain should be achievable [9].
Cachexia Cachexia is the cytokine-induced wasting of protein and energy stores caused by the effects of disease. Systemic inflammation mediated through cell injury or activation of the immune system triggers an acute inflammatory response. This response is the most common cause of anorexia observed in the acute care setting [10]. Cytokines are related to a number of disease conditions, including cancer [11], end-stage renal disease [12], chronic pulmonary disease [6], congestive heart failure [13], rheumatoid arthritis [14], and AIDS [15]. Cytokines directly result in feeding suppression and lower intake of nutrients. Interleukin-1b (IL-1b) and tumor necrosis factor (TNF) act on the glucose-sensitive neurons in the ventromedial hypothalamic nucleus (a ‘‘satiety-detecting’’ site) and the lateral hypothalamic area (a ‘‘hunger-detecting’’ site) [10,16,17]. The relationship of cytokines to anorexia is complex. Although the cancer anorexia-cachexia syndrome is present in 50% of advanced cancer patients and in 80% of terminally ill cancer patients, serum levels of cytokines are not always directly associated with the onset of the cancer anorexia-cachexia syndrome [18]. In patients with pneumonia, the admission concentrations of alpha1-antitrypsin and alpha1-acid glycoprotein are better predictors of hospital morbidity than are albumin and C-reactive protein levels [6]. In patients with end-stage renal disease receiving hemodialysis who were followed for 3 years, increased IL-1, TNF-a, IL-6, and IL-13 levels were significantly associated with increased relative mortality risk, whereas higher levels of IL-2, IL-4, IL-5, IL-12, T-cell number and function, and CH50 were associated with improved survival rates [19]. Elevated cytokine levels have been implicated in the weight loss associated with HIV infection and are independent of immune status [20]. The data suggest that cytokine levels are commonly associated with disease conditions characterized by cachexia and may be involved in mortality, weight loss, and appetite suppression. Unlike starvation, cachexia is remarkably resistant to hypercaloric feeding. The provision of additional calories and protein alone has not been shown to be efficacious in patients with cancer cachexia [21].
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Distinguishing starvation and cachexia Generally, nutritional problems are identified using various biochemical or anthropometric parameters, including body weight [22], the body-mass index [23], mid-arm circumference or triceps skin-fold thickness [24,25], serum concentrations of proteins produced by the liver [26], grip strength [27], anergy [28], and immunologic functions [29]. No single measurement is highly sensitive and specific in identifying undernutrition [30,31]. A limitation of these biochemical and anthropormetric variables is that they are not specific for nutritional status [26,29]. For example, hypoalbuminemia occurs in disease states such as hepatic disease, renal disease, congestive heart failure [32], and stress [33] and decreases after 8 hours of bed rest [34]. Frequently, these biochemical parameters are attributed to nutritional status, and their relationship to an underlying disease is ignored. Abnormalities in serum albumin levels ( < 35 g/L) and lymphocyte count ( < 1500 cells/mL) have been used as an ‘‘instant nutritional assessment.’’ Only 3.4% of patients admitted to a general hospital ward had a low nutritional index, whereas 21.5% of persons admitted to the intensive care unit had low values [35]. This finding suggests that the index may be a measure of severity of illness rather than nutritional status. Cachexia is associated with inflammatory or neoplastic conditions that produce an acute-phase cytokine response. There is a strong inverse correlation between soluble interleukin-2R (sIL-2R) and frequently used nutritional parameters including albumin, prealbumin, cholesterol, transferrin, and hemoglobin levels [36]. Because of the high correlation between sIL-2R and nutritional parameters, it is not surprising that sIL-2R is a better predictor of mortality after adjusting for albumin, prealbumin, C-reactive protein, and hemoglobin levels, even though each of these factors is univariately a significant predictor [37]. Cholesterol is lowered in the presence of proinflammatory cytokines such as IL-6 [38]. It is possible that commonly described biochemical and anthropometric variables do not measure nutritional status [30]. Labeling these factors as nutritionrelated may lead to confusion in addressing nutritional status. For example, although it is clear that lower total lymphocyte count is strongly associated with adverse outcomes, it is not clear that lower total lymphocyte count is related to nutritional status. When total lymphocyte count was compared with body composition studies as a means of nutritional assessment, the total lymphocyte count correlated poorly with both the body cell mass and the nutritional state measured by the Nae:Ke ratio. The total lymphocyte count had a false-positive rate of 34% and a false-negative rate of 50% for diagnosing undernutrition [39]. The common pathway causing a reduction in serum albumin and serum cholesterol levels may result from cytokine induction rather than from the absence of nutrients. Using the serum albumin or serum cholesterol level as a marker of inflammation is easier and less expensive than measuring serum cytokines. The use of albumin and cholesterol levels as nutritional parameters in these patients could potentially lead to overdiagnosis of undernutrition, however [36].
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Commonly used nutritional parameters differ in several respects in simple starvation compared with pathologic disease states. The serum albumin level remains normal in short-term and long-term fasting [40,41]. In fact, after 9 weeks on a diet of about half the normal dietary intake of protein (0.45 g/kg/day), the serum albumin level remained normal despite changes in lean body mass and immune status [42]. Serum albumin levels remain normal in patients with anorexia nervosa, a condition of chronic energy deficiency, and serum cholesterol levels increase in one third of anorexia patients. Chronic inadequate intake of protein (kwashiorkor) does lead to a decline in serum albumin levels. Body mass index decreases with starvation. Body mass index alone, however, is a poor predictor of mortality in starved individuals, even when starvation is severe. In starving individuals who are re-fed, a body mass index below 13.5 was not predictive of mortality [43], perhaps because the body mass index does not distinguish between fat mass and lean body mass. The inability of the body mass index to assess nutrition reserves may account for its poor performance in assessing starvation [44,45]. On the other hand, the body mass index is an important predictor of mortality among hospitalized patients. A low body mass index is associated with increased mortality [46,47], even after controlling for recent weight loss, serum albumin level, severity of illness as measured by the Acute Physiology and Chronic Health Evaluation score, and patient demographics [48]. This finding suggests that the predictive significance of a low body mass differs i in starvation and cachexia states. The proportion of B lymphocytes is lower in starving children than in normally nourished children [49]. Improvement in the ratio of lymphocyte subsets has been reported at 40 days after refeeding [50]. Following nutritional supplementation, a 13.4% increase in number of T cells has been reported at 6 months [51], but it is not clear whether the change is related to the intervention or to other unmeasured factors. In cachexia, little evidence for an increase in lymphocyte count has been demonstrated.
Nutritional interventions The first response of caregivers to clinical signs of undernutrition, whether caused by starvation or cachexia, is to increase nutrient intake. A large number of nutritional interventions have been directed towards improving intake. Despite demonstrating an increase in nutrient delivery, clinical trials have shown disappointing results in improving clinical outcome [52]. The poor response of these patients to hypercaloric feeding suggests that a different mechanism may be operative. A 20% decline in lean body mass has been shown in critically ill patients, despite aggressive caloric support [53]. In malnourished or high-risk surgical patients, enteral or parenteral support has not reduced the risk of postoperative complications to that of well-nourished patients undergoing similar procedures
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[54]. Improvements in nutritional markers, such as serum protein concentrations, nitrogen balance, and weight gain, have not usually been accompanied by objective clinical benefits [55]. Although there is a strong relationship between the absence of a cutaneous delayed hypersensitivity response and mortality, nutritional support has failed to correct cellular immune dysfunction [28]. Improvement in nutritional parameters has been demonstrated in small numbers of parenterally fed hospitalized patients with protein-energy undernutrition [56]. Older persons, however, respond poorly to aggressive nutritional therapy. In a study of 325 nutritionally at-risk patients receiving total parenteral nutrition, 219 patients showed improvement in body cell mass with parenteral feedings, and 106 patients showed no change in body cell mass with feedings. The outcome in older patients was dismal. In the 179 patients over the age of 65 years, no statistically significant improvement in body weight, body fat, lean body mass, extracellular mass, or body cell mass occurred [57]. Interventions to encourage voluntary consumption of adequate calories have been marginally effective in anorexic patients. In a meta-analysis of 15 randomized, controlled clinical trials of dietary advice with or without nutritional supplements, no difference in mortality was observed (relative risk [RR], 0.33; 95% confidence interval [CI], 0.04 –2.99]. The nutritionally supplemented group, but not the group receiving dietary advice alone, had a small gain in weight at 3 months (weighted mean difference 1.14 kg; (95% CI, 1.94, 0.33), but no difference was seen at 6 months [58]. In a trial of nutritional supplementation, 87 consecutive patients were randomly assigned to receive a glucose drink containing vitamin A, B1, B2, B3, and B6 supplements or placebo. Compliance was poor, with only one third of participants consuming more than 50% of the offered drink. Even when the analysis was limited to compliant subjects, no beneficial effect was observed [59]. Exercise and nutritional supplements have been combined in an intervention trial. In 100 long-term care residents aged 87.1 ± 0.6 years randomly assigned to high-intensity exercise training, a subgroup was further randomly assigned to receive 240 mL of nutritional supplementation. Although muscle strength increased by 113% ± 8% in the training group, the addition of a nutritional supplement did not improve outcome [60]. Oral multinutrient feedings (providing nonprotein energy, protein, and some vitamins and minerals) have been evaluated in a meta-analysis of five trials. Oral hypercaloric feeding reduced subsequent complications (RR, 0.52; 95% CI, 0.32 –0.84), but had no effect on mortality (RR, 0.85; 95% CI, 0.42 –1.70). A meta-analysis of three trials has shown no evidence that protein in an oral feeding affects mortality (RR, 1.38; 95% CI, 0.82 –2.34). Use of supplements may have reduced the number of long-term complications and days spent in rehabilitation wards [61]. The strongest evidence for the effectiveness of nutritional supplementation exists for oral protein and energy feedings, but the evidence is still very weak. Improvement in clinical outcome in the long-term care setting is even more difficult to document. In a study of undernourished patients admitted to a nursing
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home, 37% of patients remained malnourished and continued to lose weight during their stay, despite aggressive efforts to increase nutrient intake [31]. At best, small gains in weight have been shown, but improvement in other commonly accepted parameters of undernutrition are difficult to demonstrate. Ciocon reported the long-term effects of enteral feedings in a long-term care setting [62]. Fifty-six enterally fed residents aged 65 to 95 years were studied prospectively for 11 months. Weight remained stable for 6 months, but weight loss was apparent beyond 6 months. Only 6% of patients gained weight at any time. The mean hemoglobin concentration remained stable during the 11-month follow up but did not increase over the mean at the start of the study. Serum albumin and hemoglobin concentration stabilized at 3 months but did not reach normal levels. Twenty-eight patients died, for a mortality rate of 46%. Most deaths occurred between the second and sixth months of enteral feeding. Aspiration pneumonia probably contributed to death in 40% of the patients who died. Survival does not seem to be affected by enteral feeding. In 1386 nursing home residents older than 65 years with recent progression to severe cognitive impairment, 9.7% of patients had a feeding tube placed. The 24-month survival rate was the same for residents who were tube fed and those who were not [63]. In community settings, improvements in body weight and skin-fold thickness have been shown over 13 weeks in malnourished patients with emphysema. The magnitude of the difference was small: a mean gain of 1.5 kg in weight and 2.7 mm in skin-fold thickness. Other indices of well-being, including pulmonary functions and immunologic status, did not improve [64].
Summary The poor response to hypercaloric feeding in ill adults may be caused by failure to distinguish cachexia from starvation (Table 1). The chief difference between starvation and cachexia is that refeeding reverses starvation but is less effective for cachexia. The ineffectiveness of refeeding in treating cachexia may explain some of the poor results from direct nutritional interventions in clinical
Table 1 Distinguishing starvation from cachexia
Appetite Body mass index Serum albumin Cholesterol Total lymphocyte count Cytokines Inflammatory disease Response to refeeding
Starvation
Cachexia
Suppressed in late phase Not predictive of mortality Low in late phase May remain normal Low, responds to refeeding Little data Usually not present Reversible
Suppressed in early phase Predictive of mortality Low in early phase Low Low, unresponsive to refeeding Elevated Present Resistant
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trials. Simple starvation should respond to voluntary or involuntary hypercaloric feedings. The failure to demonstrate a more positive response may be caused by underlying cachexic states.
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[45] Elia M, Stubbs RJ, Henry CJ. Differences in fat, carbohydrate, and protein metabolism between lean and obese subjects undergoing total starvation. Obes Res 1999;7:597 – 604. [46] Diehr P, Bild DE, Harris TB, et al. Body mass index and mortality in nonsmoking older adults. The Cardiovascular Health Study. Am J Public Health 1998;88:623 – 9. [47] Landi F, Onder G, Gambassi G, et al. Body mass index and mortality among hospitalized patients Arch Intern Med 2000;160:2641 – 4. [48] Galanos AN, Pieper CF, Kussin PS, et al. Relationship of body mass index to subsequent mortality among seriously ill hospitalized patients. Crit Care Med 1997;25:1962 – 8. [49] Rikimaru T, Taniguchi K, Yartey JE, et al. Humoral and cell-mediated immunity in malnourished children in Ghana. Eur J Clin Nutr 1998;52:344 – 50. [50] Gogos CA, Ginopoulos P, Salsa B, et al. Dietary omega-3 polyunsaturated fatty acids plus vitamin E restore immunodeficiency and prolong survival for severely ill patients with generalized malignancy: a randomized control trial. Cancer 1998;82:395 – 402. [51] Roebothan BV, Chandra RK. Relationship between nutritional status and immune function of elderly people. Age Ageing 1994;23:49 – 53. [52] Atkinson S, Sieffert E, Bihari D. A prospective, randomized, double-blind, controlled clinical trial of enteral immunonutrition in the critically ill. Crit Care Med 1998;26:1164 – 72. [53] Plank LK, Connolly AB, Hill GI. Sequential changes in the metabolic response in severely septic patients during the first 23 days after the onset of peritonitis. Ann Surg 1998;228: 146 – 58. [54] Campos ACL, Meguid MM. A critical appraisal of the usefulness of perioperative nutritional support. Am J Clin Nutr 1992;55:117 – 30. [55] Souba WW. Drug therapy: nutritional support. N Engl J Med 1997;336:41 – 8. [56] Lipschitz DA, Mitchell CO. The correctability of the nutritional, immune and hematopoietic manifestations of protein-calorie malnutrition in the elderly. J Am Coll Nutr 1982;1:17 – 25. [57] Shizgal HM, Martin MF, Gimmon Z. The effect of age on the caloric requirement of malnourished individuals. Am J Clin Nutr 1992;55:783 – 9. [58] Baldwin C, Parsons T, Logan S. Dietary advice for illness-related malnutrition in adults. The Cochrane Database of Systematic Reviews. The Cochrane Library, Issue 2. Oxford: Update Software; 2002. [59] Hogarth MB, Marshall P, Lovat LB, et al. Nutritional supplementation in elderly medical inpatients: a double-blind placebo-controlled trial. Age Ageing 1996;25:453 – 7. [60] Fiatarone MA, O’Neill EF, Ryan ND, et al. Exercise training and nutritional supplementation for physical frailty in very elderly people. N Engl J Med 1994;330:1769 – 75. [61] Avenell A, Handoll HHG. Nutritional supplementation for hip fracture aftercare in the elderly. In: Cochrane Database of Systematic Reviews. The Cochrane Library, Issue 2, 2001. Oxford: Update Software; 2002. [62] Ciocon JO, Silverstone FA, Graver LM, et al. Tube feedings in elderly patients: indications, benefits, and complications. Arch Intern Med 1988;148:429 – 33. [63] Mitchell SL, Kiely DK, Lipsitz LA. The risk factors and impact on survival of feeding tube placement in nursing home residents with severe cognitive impairment. Arch Intern Med 1997; 157:327 – 32. [64] Otte KE, Ahlburg P, D’Amore F, et al. Nutritional repletion in malnourished patients with emphysema. Journal of Parentral and Enteral Nutrition 1989;13:152 – 6.
Distinguishing starvation from cachexia David R. Thomas, MD, FACP, FAGS Division of Geriatric Medicine, Saint Louis Health Sciences Center, 1402 South Grand Boulevard M238, Saint Louis, MO 63140, USA
Starvation Simple starvation is caused by pure protein-energy deficiency. Starvation can be short-term (fasting) or long-term (chronic protein-energy undernutrition). Worldwide, starvation is most often caused by lack of food. In developed countries, undernutrition is most often related to medical causes. Obviously, failure to ingest adequate nutrients leads to undernutrition. Starvation occurring in the presence of adequate food can result from inability to swallow, a nonfunctioning gastrointestinal tract, or failure of appetite (anorexia). Strategies for involuntarily increasing the intake of nutrients include enteral or parenteral feeding. Increasing voluntary consumption of nutrients is more problematic. Appetite regulation is affected by illness, drugs, dementia, and mood disorders [1– 3]. Anorexia may be a physiologic response to aging, resulting from changes in the physiologic regulation of appetite and satiety [4]. Acute illness is characterized by a spontaneous decrease in food intake despite an increased need for energy and nutrients [5]. Although seemingly paradoxical, the voluntary suppression of food intake during illness is common to most species [6]. The reduction in food intake accompanying acute illness occurs both before and during hospitalization. In a prospective study of elderly people, 65% of the men and 69% of the women had an insufficient energy intake in the month before hospitalization. Undernutrition was present in 52.9% of men and 60.6% of women by the time of admission to the hospital [7]. This reduction in nutrient and energy intake at the beginning of an acute illness predisposes a patient to a risk for worsening undernutrition during hospitalization. Inadequate intake of nutrients continues during hospitalization. In 286 general medical patients, 27% became malnourished after hospital admission (defined as an post-admission reduction in mid-arm circumference of 3.6%). These patients were more likely to consume less than 40% of prescribed food and were more likely to have lower Mini-Mental Status Examination scores, functional impair-
E-mail address: [email protected] (D.R. Thomas). 0749-0690/02/$ – see front matter D 2002, Elsevier Science (USA). All rights reserved. PII: S 0 7 4 9 - 0 6 9 0 ( 0 2 ) 0 0 0 3 2 - 0
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D.R. Thomas / Clin Geriatr Med 18 (2002) 883–891
ment, lower total lymphocyte counts, and lower serum albumin levels than patients who were not malnourished [8]. Descriptive studies have shown that older adults with clinical or biochemical markers for undernutrition have poor outcomes. A reversal of illness-related anorexia or clinical benefit from hypercaloric feeding has been difficult to demonstrate, however. The observed reduction in food intake in ill older adults may be a physiologic adaptation to illness. The reduction in food intake is often equated with starvation. Starvation caused by inadequate availability of nutrients responds to hypercaloric feeding in both children and adults. If absorption is intact, provision of nutrients can be expected to reverse starvation. In starvation, repletion of serum albumin, cholesterol, improved immune function, and weight gain should be achievable [9].
Cachexia Cachexia is the cytokine-induced wasting of protein and energy stores caused by the effects of disease. Systemic inflammation mediated through cell injury or activation of the immune system triggers an acute inflammatory response. This response is the most common cause of anorexia observed in the acute care setting [10]. Cytokines are related to a number of disease conditions, including cancer [11], end-stage renal disease [12], chronic pulmonary disease [6], congestive heart failure [13], rheumatoid arthritis [14], and AIDS [15]. Cytokines directly result in feeding suppression and lower intake of nutrients. Interleukin-1b (IL-1b) and tumor necrosis factor (TNF) act on the glucose-sensitive neurons in the ventromedial hypothalamic nucleus (a ‘‘satiety-detecting’’ site) and the lateral hypothalamic area (a ‘‘hunger-detecting’’ site) [10,16,17]. The relationship of cytokines to anorexia is complex. Although the cancer anorexia-cachexia syndrome is present in 50% of advanced cancer patients and in 80% of terminally ill cancer patients, serum levels of cytokines are not always directly associated with the onset of the cancer anorexia-cachexia syndrome [18]. In patients with pneumonia, the admission concentrations of alpha1-antitrypsin and alpha1-acid glycoprotein are better predictors of hospital morbidity than are albumin and C-reactive protein levels [6]. In patients with end-stage renal disease receiving hemodialysis who were followed for 3 years, increased IL-1, TNF-a, IL-6, and IL-13 levels were significantly associated with increased relative mortality risk, whereas higher levels of IL-2, IL-4, IL-5, IL-12, T-cell number and function, and CH50 were associated with improved survival rates [19]. Elevated cytokine levels have been implicated in the weight loss associated with HIV infection and are independent of immune status [20]. The data suggest that cytokine levels are commonly associated with disease conditions characterized by cachexia and may be involved in mortality, weight loss, and appetite suppression. Unlike starvation, cachexia is remarkably resistant to hypercaloric feeding. The provision of additional calories and protein alone has not been shown to be efficacious in patients with cancer cachexia [21].
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Distinguishing starvation and cachexia Generally, nutritional problems are identified using various biochemical or anthropometric parameters, including body weight [22], the body-mass index [23], mid-arm circumference or triceps skin-fold thickness [24,25], serum concentrations of proteins produced by the liver [26], grip strength [27], anergy [28], and immunologic functions [29]. No single measurement is highly sensitive and specific in identifying undernutrition [30,31]. A limitation of these biochemical and anthropormetric variables is that they are not specific for nutritional status [26,29]. For example, hypoalbuminemia occurs in disease states such as hepatic disease, renal disease, congestive heart failure [32], and stress [33] and decreases after 8 hours of bed rest [34]. Frequently, these biochemical parameters are attributed to nutritional status, and their relationship to an underlying disease is ignored. Abnormalities in serum albumin levels ( < 35 g/L) and lymphocyte count ( < 1500 cells/mL) have been used as an ‘‘instant nutritional assessment.’’ Only 3.4% of patients admitted to a general hospital ward had a low nutritional index, whereas 21.5% of persons admitted to the intensive care unit had low values [35]. This finding suggests that the index may be a measure of severity of illness rather than nutritional status. Cachexia is associated with inflammatory or neoplastic conditions that produce an acute-phase cytokine response. There is a strong inverse correlation between soluble interleukin-2R (sIL-2R) and frequently used nutritional parameters including albumin, prealbumin, cholesterol, transferrin, and hemoglobin levels [36]. Because of the high correlation between sIL-2R and nutritional parameters, it is not surprising that sIL-2R is a better predictor of mortality after adjusting for albumin, prealbumin, C-reactive protein, and hemoglobin levels, even though each of these factors is univariately a significant predictor [37]. Cholesterol is lowered in the presence of proinflammatory cytokines such as IL-6 [38]. It is possible that commonly described biochemical and anthropometric variables do not measure nutritional status [30]. Labeling these factors as nutritionrelated may lead to confusion in addressing nutritional status. For example, although it is clear that lower total lymphocyte count is strongly associated with adverse outcomes, it is not clear that lower total lymphocyte count is related to nutritional status. When total lymphocyte count was compared with body composition studies as a means of nutritional assessment, the total lymphocyte count correlated poorly with both the body cell mass and the nutritional state measured by the Nae:Ke ratio. The total lymphocyte count had a false-positive rate of 34% and a false-negative rate of 50% for diagnosing undernutrition [39]. The common pathway causing a reduction in serum albumin and serum cholesterol levels may result from cytokine induction rather than from the absence of nutrients. Using the serum albumin or serum cholesterol level as a marker of inflammation is easier and less expensive than measuring serum cytokines. The use of albumin and cholesterol levels as nutritional parameters in these patients could potentially lead to overdiagnosis of undernutrition, however [36].
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Commonly used nutritional parameters differ in several respects in simple starvation compared with pathologic disease states. The serum albumin level remains normal in short-term and long-term fasting [40,41]. In fact, after 9 weeks on a diet of about half the normal dietary intake of protein (0.45 g/kg/day), the serum albumin level remained normal despite changes in lean body mass and immune status [42]. Serum albumin levels remain normal in patients with anorexia nervosa, a condition of chronic energy deficiency, and serum cholesterol levels increase in one third of anorexia patients. Chronic inadequate intake of protein (kwashiorkor) does lead to a decline in serum albumin levels. Body mass index decreases with starvation. Body mass index alone, however, is a poor predictor of mortality in starved individuals, even when starvation is severe. In starving individuals who are re-fed, a body mass index below 13.5 was not predictive of mortality [43], perhaps because the body mass index does not distinguish between fat mass and lean body mass. The inability of the body mass index to assess nutrition reserves may account for its poor performance in assessing starvation [44,45]. On the other hand, the body mass index is an important predictor of mortality among hospitalized patients. A low body mass index is associated with increased mortality [46,47], even after controlling for recent weight loss, serum albumin level, severity of illness as measured by the Acute Physiology and Chronic Health Evaluation score, and patient demographics [48]. This finding suggests that the predictive significance of a low body mass differs i in starvation and cachexia states. The proportion of B lymphocytes is lower in starving children than in normally nourished children [49]. Improvement in the ratio of lymphocyte subsets has been reported at 40 days after refeeding [50]. Following nutritional supplementation, a 13.4% increase in number of T cells has been reported at 6 months [51], but it is not clear whether the change is related to the intervention or to other unmeasured factors. In cachexia, little evidence for an increase in lymphocyte count has been demonstrated.
Nutritional interventions The first response of caregivers to clinical signs of undernutrition, whether caused by starvation or cachexia, is to increase nutrient intake. A large number of nutritional interventions have been directed towards improving intake. Despite demonstrating an increase in nutrient delivery, clinical trials have shown disappointing results in improving clinical outcome [52]. The poor response of these patients to hypercaloric feeding suggests that a different mechanism may be operative. A 20% decline in lean body mass has been shown in critically ill patients, despite aggressive caloric support [53]. In malnourished or high-risk surgical patients, enteral or parenteral support has not reduced the risk of postoperative complications to that of well-nourished patients undergoing similar procedures
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[54]. Improvements in nutritional markers, such as serum protein concentrations, nitrogen balance, and weight gain, have not usually been accompanied by objective clinical benefits [55]. Although there is a strong relationship between the absence of a cutaneous delayed hypersensitivity response and mortality, nutritional support has failed to correct cellular immune dysfunction [28]. Improvement in nutritional parameters has been demonstrated in small numbers of parenterally fed hospitalized patients with protein-energy undernutrition [56]. Older persons, however, respond poorly to aggressive nutritional therapy. In a study of 325 nutritionally at-risk patients receiving total parenteral nutrition, 219 patients showed improvement in body cell mass with parenteral feedings, and 106 patients showed no change in body cell mass with feedings. The outcome in older patients was dismal. In the 179 patients over the age of 65 years, no statistically significant improvement in body weight, body fat, lean body mass, extracellular mass, or body cell mass occurred [57]. Interventions to encourage voluntary consumption of adequate calories have been marginally effective in anorexic patients. In a meta-analysis of 15 randomized, controlled clinical trials of dietary advice with or without nutritional supplements, no difference in mortality was observed (relative risk [RR], 0.33; 95% confidence interval [CI], 0.04 –2.99]. The nutritionally supplemented group, but not the group receiving dietary advice alone, had a small gain in weight at 3 months (weighted mean difference 1.14 kg; (95% CI, 1.94, 0.33), but no difference was seen at 6 months [58]. In a trial of nutritional supplementation, 87 consecutive patients were randomly assigned to receive a glucose drink containing vitamin A, B1, B2, B3, and B6 supplements or placebo. Compliance was poor, with only one third of participants consuming more than 50% of the offered drink. Even when the analysis was limited to compliant subjects, no beneficial effect was observed [59]. Exercise and nutritional supplements have been combined in an intervention trial. In 100 long-term care residents aged 87.1 ± 0.6 years randomly assigned to high-intensity exercise training, a subgroup was further randomly assigned to receive 240 mL of nutritional supplementation. Although muscle strength increased by 113% ± 8% in the training group, the addition of a nutritional supplement did not improve outcome [60]. Oral multinutrient feedings (providing nonprotein energy, protein, and some vitamins and minerals) have been evaluated in a meta-analysis of five trials. Oral hypercaloric feeding reduced subsequent complications (RR, 0.52; 95% CI, 0.32 –0.84), but had no effect on mortality (RR, 0.85; 95% CI, 0.42 –1.70). A meta-analysis of three trials has shown no evidence that protein in an oral feeding affects mortality (RR, 1.38; 95% CI, 0.82 –2.34). Use of supplements may have reduced the number of long-term complications and days spent in rehabilitation wards [61]. The strongest evidence for the effectiveness of nutritional supplementation exists for oral protein and energy feedings, but the evidence is still very weak. Improvement in clinical outcome in the long-term care setting is even more difficult to document. In a study of undernourished patients admitted to a nursing
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home, 37% of patients remained malnourished and continued to lose weight during their stay, despite aggressive efforts to increase nutrient intake [31]. At best, small gains in weight have been shown, but improvement in other commonly accepted parameters of undernutrition are difficult to demonstrate. Ciocon reported the long-term effects of enteral feedings in a long-term care setting [62]. Fifty-six enterally fed residents aged 65 to 95 years were studied prospectively for 11 months. Weight remained stable for 6 months, but weight loss was apparent beyond 6 months. Only 6% of patients gained weight at any time. The mean hemoglobin concentration remained stable during the 11-month follow up but did not increase over the mean at the start of the study. Serum albumin and hemoglobin concentration stabilized at 3 months but did not reach normal levels. Twenty-eight patients died, for a mortality rate of 46%. Most deaths occurred between the second and sixth months of enteral feeding. Aspiration pneumonia probably contributed to death in 40% of the patients who died. Survival does not seem to be affected by enteral feeding. In 1386 nursing home residents older than 65 years with recent progression to severe cognitive impairment, 9.7% of patients had a feeding tube placed. The 24-month survival rate was the same for residents who were tube fed and those who were not [63]. In community settings, improvements in body weight and skin-fold thickness have been shown over 13 weeks in malnourished patients with emphysema. The magnitude of the difference was small: a mean gain of 1.5 kg in weight and 2.7 mm in skin-fold thickness. Other indices of well-being, including pulmonary functions and immunologic status, did not improve [64].
Summary The poor response to hypercaloric feeding in ill adults may be caused by failure to distinguish cachexia from starvation (Table 1). The chief difference between starvation and cachexia is that refeeding reverses starvation but is less effective for cachexia. The ineffectiveness of refeeding in treating cachexia may explain some of the poor results from direct nutritional interventions in clinical
Table 1 Distinguishing starvation from cachexia
Appetite Body mass index Serum albumin Cholesterol Total lymphocyte count Cytokines Inflammatory disease Response to refeeding
Starvation
Cachexia
Suppressed in late phase Not predictive of mortality Low in late phase May remain normal Low, responds to refeeding Little data Usually not present Reversible
Suppressed in early phase Predictive of mortality Low in early phase Low Low, unresponsive to refeeding Elevated Present Resistant
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trials. Simple starvation should respond to voluntary or involuntary hypercaloric feedings. The failure to demonstrate a more positive response may be caused by underlying cachexic states.
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