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NUTRITION AND COPD Gary L. Huber, M.D., Rick Carter, Ph.D. and Mary Burke-Huber, R.T.T. University of Texas Health Center Tyler, Texas 75 710

Nutrition and COPD Chronic obstructive pulmona .ry disease (COPD) is the term given to the disorder that occurs in patients who have a limitation of airflo~v that persists over time. Characteristically, the airflow obstruction is most evident on expiration, and can be quantified easily by standard spirometry in a physician's office, at the hospital bedside, or in a pulmonary function laboratory. The obstruction to airflow is not significantly reversed by inhalation of a bronchodilator drug. Generally, the connotation COPD is commonly employed to include chronic bronchitis, emphysema, bronchiectasis, and small airways disease. Thurlbeck and others have emphasized, however, that patients with chronic airflow obstruction cannot usually be classified readily into these precise "subcategories," in that a wide spectrum of airway and parench,vmal pathology exists among patients with COPD and varies from patient to pauent . Epidemiology and Pathogenesis. COPD is a common disease. Recent national __.~_~_~rev.a.lence data are not available, but extrapolation_of assessments derived within the past decade estimate that there are more than 1 9 million Americans with COPD ~2~. This is comparable, by one evaluation, to about 1 4 percent of the adult male and 8 percent of the adult female population~31. Accurate prevalence data, however, are hard to come by, and some would place the true magnitude of the disease at a higher level. COPD often is a debilitating disorder. It accounts each year for an estimated 1 7 million or probably more annual office visits and over 2 million hospitalizationsTM. COPD is the second leading cause of disability in the United States, and the fifth most common cause of death. The duration of hospitalization of patients with exacerbations

Nutrition and COPD of COPD is approximately 50 percent longer than is the duration of hospitalization for the general population. Patients with COPD have about twice the amount of annual disability and restricted activity, compared to the general adult population, and the cost to the American economy in health care and in loss of productivity is enormous. The most important risk factors that have been reported for the development of COPD include a history, of tobacco cigarette smoking, age, air pollution, occupational exposures, male sex, alpha-l-antiprotease deficiency, and childhood respiratory illness. Other potentially important contributing risk factors include socioeconomic status, inherent airway reactivity, a history of atopy, alcohol intake, and other lifestyle behaviors. Prevalence rates for COPD are most strongly influenced by a history of tobacco smoking, with 15 percent to as high as 50 percent of smokers reporting ~symptoms of "smoker's cough" or chronic bronchitis (persistent cough and sputum production), ..__._.c9..~p~ed to a much lower rate (3% to 6%) of these symptoms in the nonsmoking populationIsz). Only about 15 percent of smokers, however, develop disabling obstructive airflow disease15), raising questions regarding genetic predisposition, inter- personal variations, influence of childhood exposure, and other factors. Pathogenesis and Natural History.. Extensive research has been conducted on the pathogenesis and natural history of COPD, giving rise to two dominant theories. One, the "British hypothesis," is based strongly on the role of pulmonary infections and exposures to inhaled irritants as key mediators in the development of COPD. The other,

Nutrition and COPD the "Dutch '., " " . m pothes~s, focuses on the role of airxvav reactivity and hypersensitivity in response to inhaled irritating substances in the pathogenesis of COPD. With ageing, the normal lung of nonsmokers progressively loses structure and function, the latter at the rate of about 20 to 40 ml/year of the forced expiratory volume at one minute (FEV~) in nonsmoking males, from age B0 to 5c~6); the rate of decline diminishes . Smokers, accelerates after about age 45, but in older age the rate of decline _ (7) in general, lose lung function at a somewhat greater rate (44 to 55 ml/yr of FEV~) and a susceptible minority of smokers have a more accelerated rate of decline (70 to 120 ml/yr of FEV~). Furthermore, it appears that the pulmonary function of individuals "tracks over time," meaning that those who have low levels of function in childhood usually will have lower levels over the further course of their life, and those who lose lung function more rapidly in their earlier years may be susceptible to an accelerated decline ..... ~vith ageingIs'9). Some studies indicate that these changes in lung function "plateau," or remain stable, through a certain period of early and middle-aged adulthood~°). The duration of this plateau may infl.uence, or even determine, the susceptibility of an individual to the later development of clinically significant COPD. For instance, a susceptible smoker may have a shorter plateau, and thus an earlier and greater decline in lung function, than a less susceptible smokert~t). For the susceptible smoker, the rate of decline in lung function bears a relationship to duration and amount of smoking (pack-years), with ~ loss of about 7 ml to 8 ml of FEVt per pack-year of cigarette consumption~21.

Nutrition and COPD Nutrition and the Developing Lung. Nutrition (especially undernutrition and/or malnutrition) has been a topic of developmental concern. The lungs of the patient ~4th COPD can be viewed in a continuum, starting with their earliest prenatal development through the very end stages of the disease. In this continuum, the integrity of the human lung is dependent on good nutrition from the beginning to the end1'31. In its earliest development, lung growth and the ultimate number of lung cells that eventually develop are reduced when nutrient intake is diminished, either in vitro or in early life. This reduction in cellular number, quantified by DNA and RNA analyses, may be permanent, and it is not yet clear whether later "catch-up" lung growth can occur. The role that any nutritionally-induced developmental abnormalities, and the associated nutritionallv- influenced genetic imprinting for ultimate susceptibility, might play in rendering the adult lung ultimately vulnerable to the development of COPD is, at this time, conjectural. If, however,, lung structure and function do indeed fu]iy "track" over time 18.9~ and if the adult "plateau" in pulmonary structure and function are determined, in part, by nutritional factors in early development/L°l, the susceptibility of the adult lung to destruction by tobacco smoke and other factors may be to some degree preprogrammed early in life by a relationship of genetic propensity interacting with nutritional and other environmental factors. Protein-calorie malnutrition, as well as vitamin-mineral micronutrient malnutrition, do at any stage of life significantly adversely effect the various components of connective tissue in the lung~'3'~4). Collagen, proteoglycans, fibronectin, laminin, and

Nutrition and COPD chondronectin are important for normal cellular growth, adhesion, migration and morphology in the developing lung. Malnutrition reduces the synthesis of key proteins inherently necessary to these processes. In experimentally induced protein-calorie malnutrition, there is a net decrease in alveolar number and total internal surface area, with an increase in alveolar size(15'16), constituting morphologic changes consistent with the definition of emphysema~17~. The micronutrients copper, zinc, pyridoxine, ascorbic acid, vitamin E and vitamin A are all important to the integrity of the lungs(~3). Copper deficiency induces morphologic lesions with abnormally diluted terminal air spaces and a fragmented, greatly altered elastin meshwork; these lesions appear to be due to impaired collagen and elastin maturation and development. Pyridoxine deficiency is associated with similar, but usually less severe, results. Ascorbic acid, vitamin E, and vitamin A (primarily as its precursor, beta-carotene) are integrally important to the antioxidant defenses against lung injury at all stages of life. Nutrition and Adult Lung Injury. A recent symposium was convened, and a subsequent monograph published, to address the influence of nutrition on tobacco- associated health risks, including COPD~). Tobacco smoke exposure is the strongest risk factor associated with the development of small airways disease, chronic bronchitis, and emphysema. Pathophysiologic mechanisms employed to explain this relationship are multifactorial, but the more prominent emerging theories have focused on the role of oxidant injury to the airways and lung parenchyma. The potential oxidant injury

Nutrition and COPD associated with smoking has at least two maior theoretical components. First, the fleshly-generated mainstream tobacco smoke that the consumer of cigarettes inhales is initially rich in free radicals and a number of oxidant species. These oxidants are very. unstable, and whether or not they reach the distal lung parenchyma is as yet unknown. It is assumed, however, that inhalation of tobacco smoke may provide the lung with a large burden of oxidant molecules potentially capable of inducing injury over time. The second potential pathogenic mechanism for inducing lung injury by cigarette consumption involves the activation of intrapulmonary defense cells, particularly the pulmonary alveolar macrophage and polymorphonuciear leukocytes that are recruited from the_cir~culation to the lung parenchyma and alveolar spaces following exposure to tobacco smoke. These inflammatory cells become activated, presumably in response to the physical or chemical particulate load delivered to the lung by smoking. During the process of ingesting, or phagocytizing, foreign particles, these inflaimmatory cells release additional reactive oxidant molecules. The body normally has adequate levels of anti- oxidant compounds on board to neutralize these reactive species. However, with a long- term, chronic process, especially when undemutrition is present, the anti-oxidant defense mechanisms are compromised. This may be especially true when recurring acute exacerbations of COPD are present. When the reactive oxidants generated by these intrapulmonary defense cells interact with the lung parenchyma and airways, tissue damage can ensue.

Nutrition and COPD There is now extensive literature reporting that the dietary, patterns of smokers, as a general group, are unhealthy, compared to nonsmokers; these studies have been summarized recently"91. Some of these studies reveal consistent trends -- the more an individual smokes, the worse, in general, is his/her dietary intake1~9221. Of significant note, smokers tend to be most deficient in their dietary intake of those nutrients they perhaps need the most - the anti-oxidants beta-carotene (and vitamin A), ascorbic acid, vitamin E, folate, pyridoxine, and other related micronutrients, including zinc and copper. Smokers generally do not consume adequate amounts of the natural fruits and vegetables which supply many of the important vitamins and trace elements. Furthermore, smokers have. higher intakes of alcohol, cholesterol and other fats, and coffee. The importance of these observations to the identification of those individuals most susceptible to developing significant COPD remains to be determined, but it is clear that understanding the biology of micronutrients will be key-to clarification of the genetic expression of disease susceptibility. Obesity. and the Patient with COPD. One most commonly thinks of weight loss and malnutrition when the nutritional status of COPD patients is considered. It must not be forgotten, however, that there is a group of COPD patients that are at the other end of the spectrum. Excess body weight (excess fat) and obesity are a problem for some patients with COPD. With excess body weight and a resultant limitation in ventilation, dyspnea is increased, predisposing the obese COPD patient to deconditioning and additional weight (fat) gain. Excess body weight in the abdomen displaces the

Nutrition and COPD diaphragm upxvard and increases the work of breathing. These patients often consume high caloric foods with little nutritional value, and as a result may additionally experience trace element malnutrition. Patients with COPD, who have excess body fat, should be counseled regarding weight reduction, improved eating habits, and exercise. With weight loss, the work of breathing will be reduced and dyspnea will lessen. With improved eating habits, trace element deficits may be restored. Exercise training will assist the patient with control of body weight and foster better eating habits. Exercise training will also improve muscle function, lessen dyspnea, and promote increased activities of daily living. Weight Loss and the Patient with COPD. COPD often becomes a severely debilitating disease. An association between weight loss, undernutrition/malnutrition and advanced stages of COPD has been recognized for over three decades. In the absence of edema or dehydration, body weight provides one-reasonable index of nutritional status. Body weights of less than 90 percent of predicted ideal body weight indicate undernutrition/malnutrition1231. By this criterion, up to 40 percent of patients (and in some evaluations up to 70 percent of patients!) with COPD are undernourished/malnourished at some point in their disease~241. A better indicator of body mass depletion is the measurement of free-fat mass. Free-fat mass can be accurately estimated using skinfolds and appropriate formulas, bioimpedence, or the "gold standard" hydrostatic weighing. However, hydrostatic weighing is not practical in a COPD clinical population. The reasons for this degree of

Nutrition and COPD malnutrition await further elucidation. Unfortunately, most existing data do not adequately define the components of body weight loss, and no study has yet defined even total caloric expenditure in COPD patients under free living conditions. Muscle wasting with COPD (especially in patients with emphysema) appears to be due to decreased protein synthesis1~3~, as well as probably other factors. There also is a marked shift in muscle fiber types from the highly fatigue resistant to those which are fatigue susceptible. Muscle weakness is generalized, and includes the diaphragm and intercostal muscles, leading to sometimes severe respiratory muscle weakness and, in the extreme, respiratory, failure. The greater the weight loss, the greater apparently is the muscle weakness in most patients. Multiple studies have revealed numerous metabolic abnormalities in the muscles of these patients, the scope of which is beyond this review. In general, however, there are low intracellular levels of ATP and energy-controlling phosphagens, leading to intracellular acidosis. Malnutrition in COPD is associated with increased morbidity and increased mortality, a greater susceptibility to infection, reduced exercise capadty, a predisposition to acute and chronic respiratory failure, and cor pulmonaleml. Hypoxemia worsens and carbon dioxide retention becomes more severe when malnutrition is present. Large dietary carbohydrate loads may increase the respiratory quotient and CO~ production in some patients. Recurrent respiratory tract infections, which are common to these patients, exacerbate protein wasting, further weakening muscle strength. This, then, 10