In industrialised countries, 4 to 6% of the male population suffers from chronic obstructive pulmonary disease (COPD). Twenty-five to 60% of subjects have a body weight lower than 90% of their ideal weight or lost 5 to10% of their initial body weight.
This weight loss is indicative of a poor prognostic. More than 40% of those who lose weight will die within five years. After five years, death rate is twice as high after weight loss compared to a stable body weight.
As a prognostic factor, weight loss is independent of forced expiratory volume in one second (FEV1). Weight loss contributes to the exhaustion state observed in some COPD patients.

COPD's, such as chronic bronchitis, emphysema and some types of chronic asthma, are characterised by progressive and irreversible lesions of the small airways and abnormal ventilation/diffusion ratio. Decrease FEV1 is the best indicator of airway obstruction and is a major predictive factor of survival.

COPD: CRITERIA FOR POOR PROGNOSTIC
Resting tachycardia Signs of chronic cor pulmonale Hypoxia Hypercapnia Decrease in FEV1:
	- FEV1 between 1,2 and 1,5 [litres s]: exertional dyspnea - FEV1 < 1 litre: - severe hypoxia, hypercapnia, - signs of chronic cor pulmonale - FEV1 < 0,5 litre : disabled patient

Losses of fat and lean body masses appear early, while the patient still has a normal and steady weight.
Similar to cachexia in cancer patients, muscle wasting in COPD is due to decreased protein synthesis following hypoxia, malnutrition and progressive reduction in physical activity.

In COPD patients, energy balance is negative and worsens during crisis. This has been explained by different causes such as insufficient food intakes, digestive malabsorption, changes in metabolism and increase in energy expenditure

Insufficient food intakes Food intake decreases in COPD patients. Eating and swallowing worsen dyspnea and arterial oxygen desaturation, especially during bouts of evolution of the disease.Further more, hypoxia and Tumor Necrosis Factor alpha (TNF - alpha) are anorexiogenic.Some studies did not observe significant differences between food intake and energy expenditure in COPD patients and concluded that food intake was insufficient.
In fact, the Harris Benedict formula was used in these studies for calculation or basal metabolic rate (BMR), and provided an under-estimated measure. BMR is more accurately assessed by indirect calorimetry.

Digestive malabsorption
Gastric, pancreatic or intestinal maldigestion or malabsorption have not been described in COPD patients.

Changes in metabolism
Food restriction induces a lower BMR and a higher rate of lipid oxidation. In catabolic states such as severe infections or burns, BMR rises with increased lipid and protein oxidation and lower carbohydrate oxidation. COPD's are not catabolic but hypermetabolic states: higher BMR is observed with increased carbohydrate and protein oxidation, leading to less protein synthesis which may partly explain the muscular fatigue in COPD patients.

Increase in energy expenditure
The total energy expended by an individual depends on the following three factors, all of which may be influenced by COPD.

ENERGY EXPENDITURE OF THE BODY

Basal metabolic rate is the energy expenditure necessary to maintain basic physiological functions. It is measured on an empty stomach, awake, at rest and in thermal neutrality. Energy expenditure for muscle tone is also taken into account. BMR represents about 1,2 kcal/minute and 60% to 80% of the total energy expenditure. Physical activity is the largest variable affecting energy expenditure and is difficult to measure. A sedentary subject is estimated to spend 15-20% of his total energy expenditure on physical activity. Thermoregulation is an increase in BMR in response to stimuli such as food, exposure to hot or cold temperature or in response to stress. Thermic effect of food (TEF) is the main component of thermoregulation and represents 5-10% of total energy expenditure. TEF comprises obligatory TEF, due to energy storage from foods, and variable TEF, due to stimulation of intermediary metabolism by new substrates.

- Basal metabolic rate
Expressed as a fraction of a theoretical value (obtained by the Harris-Benedict formulae) or as kg of lean body mass, BMR is always 10% higher in COPD patients, independently from bouts of evolution of the disease or from steady weight periods.
Is a higher BMR due to an increase in energy expenditure from respiratory efforts? In normal subjects, respiratory efforts represent 2-3% of BMR. In COPD patients, respiratory muscles have indeed a higher workload. However only resting expenditures may be included in BMR and no reliable method can assess resting respiratory energy costs. Nevertheless, it was recently shown that there is no significant relationship between increased BMR and respiratory energy expenditure.

- Physical activity
Physical activity is more energy costly in COPD patients. However, reduction or even absence of physical activity considerably reduces this type of energy expenditure.

- Thermic effect of food
Food-induced rise in energy expenditure is minimal and does not provide any explanation to weight loss in COPD patients.



IV - COPD AND HYPERMETABOLISM

Malnutrition in COPD patients is comparable to cancer or chronic cardiac insufficiency patients in hypermetabolism state.
There may be a common cause to malnutrition in these conditions rather than a mechanism specific to COPD. Common mechanisms could imply a rise in thermogenic hormones T4 and T3, endogenous catecholamines, certain treatments and cytokines. It has not been shown yet that the first three mechanisms contribute to an increased BMR. However, cytokines were identified to play a role, especially TNF-alpha.
Produced by macrophages, TNF-alpha inhibits lipoprotein-lipase and induces anorexia and fever. It promotes the release of other cytokines such as interleukin 1 and 2, which also increase energy expenditure.
Increase in TNF-alpha has been observed in COPD patients without any inflammatory syndrome and in a stable respiratory state. Opposite to any respiratory parameter (especially respiratory energy expenditure), TNF-alpha is the only parameter positively correlated to BMR.



V - IMPROVEMENT OF NUTRITIONAL STATUS IN COPD

A malnourished COPD patient is not in a catabolic state. In theory, a caloric supplementation should lead to weight gain.
Controlled studies have shown that very high caloric intakes are necessary for weight gain and are difficult to obtain in practice.
When overeating resumes, weight loss and decrease in respiratory muscular strength occur rapidly. For a few years now, growth hormone, anabolic steroids and physical activity (even if moderate) have been used in addition to caloric supplementation.

PRIMARY MEASURES TO IMPROVE NUTRITIONAL STATUS IN COPD

Increase in caloric intakes High caloric intakes are necessary for weight gain (1,7 times BMR value). They are very difficult to obtain and maintain on the medium to long-term with only ingested contributions. When patients are not encouraged to pursue this overeating regimen, they rapidly quit and fall back to an insufficient weight. Further more, weight gain is essentially as fat mass rather than as lean body mass deposit. Growth hormone Use of growth hormone in COPD patients has been shown to increase lean body mass, induce weight gain and improve nitrogen balance. Anabolic effects of growth hormone must be exerted through IGF-1. Anabolic steroids Two studies have shown intra-muscular nandralone to have a positive effect on weight gain when associated with nutritional supplements and exercise, vs nutritional supplements and exercise only. Growth hormone Use of growth hormone in COPD patients has been shown to increase lean body mass, induce weight gain and improve nitrogen balance. Anabolic effects of growth hormone must be exerted through IGF-1.

The various mechanisms involved in COPD malnutrition are not fully identified yet. Food intake is insufficient particularly in dyspneic patients. While food intake is insufficient, increased BMR and reduced protein synthesis appear to be the principal causes of malnutrition and weight loss. Weight loss in COPD's is hardly reversible and is a major indicator of a pessimistic prognostic.

Pr. FERNAND LAMISSE
CHU Tours

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