- Email: [email protected]
Why do patients with emphysema lose weight?
collective consciousness. A disease that had been "conquered" by medical science and largely confined to pockets of the third world suddenly reemerged as a global threat. Scientists were shaken out of their complacency and tuberculosis became a matter of public concern. In the UK, an ambitious research programme is being pursued under the initiative at centres in London and Birmingham, and scientists at Glaxo are conducting their own research in collaboration. In South Africa, the Medical Research Council is coordinating research programmes at various institutes throughout the country. At the London School of Hygiene and Tropical Medicine, a wideranging programme was initiated in July, 1993. Mycobacterial cell wall biosynthesis is being tackled by biochemistry and molecular biology teams. The cell wall is implicated in the virulence of the organism and is therefore a good target for novel antibiotics, and assays for enzymes involved in cell wall biosynthesis could be developed to screen new agents for their therapeutic potential. Since future treatment strategies will almost certainly depend on the combination of antimycobacterial agents with augmentation of patients’ immune response to the infection, a molecular immunology group is meanwhile dissecting the mechanisms of host immunity to Mycobacterium tuberculosis in a murine model.
Apart from the scientific progress achieved already, tangible benefits for the London School have included laboratory renovations and the appointment of new staff. The three project supervisors in London each have their counterpart at Glaxo, and the scientist-to-scientist collaborations are deemed valuable. At this juncture sceptics might reasonably ask "what’s in this for the company?". Clearly short-term goals have been eschewed, but as a public relations exercise the initiative is unquestionably a success. Moreover, Glaxo has by this means secured an impressive array of medical research expertise to sharpen its competitive edge. Although not all academic researchers would feel comfortable with such an arrangement, as an example of an effective partnership between the pharmaceutical industry and academic health sciences it has much to offer. Medical science is not outwith the public domain but part of it, and medical scientists likewise have obligations to society at large. As Polanyi opined, scientists must participate in the public debate whereby all our futures are ultimately determined. Medical researchers are ideally placed to initiate that debate, to educate the public about the special attributes of the scientific method, and to use their
creativity wisely. The Lancet
COMMENTARY
Why do patients with emphysema lose weight? Weight loss has long been recognised as a feature of advanced emphysema.’ Data obtained from a trial of intermittent positive-pressure breathing in chronic obstructive pulmonary disease (COPD) sponsored by the National Institutes of Health showed that weight loss was a common complaint among such patients and that it was associated with considerably increased morbidity and mortality.2 The relation between mortality and low body weight was not only evident in patients with severe airflow obstruction; indeed it was strongest in those with less severe disease. Attempts to limit the adverse effects of malnutrition in COPD via nutritional supplementation programmes have had little success.3
Why do patients with COPD lose weight, and why is weight loss associated more with emphysema than with bronchitis? Moreover, how is weight loss linked to a poor outcome? Until lately the most favoured explanation was a mechanistic one-the increased work of breathing in emphysematous patients resulted in increased energy expenditure, negative energy balance, and weight loss/ However, patients with COPD who lose weight are not always hypermetabolic, while patients with similar increases in the work of breathing due to other respiratory diseases do not exhibit weight loss.5 Recent experimental work has focused on the role of cytokines in the 1190
pathogenesis of weight loss.6,7 Studies of TNF-a (cachexin) in COPD patients show that not only are serum concentrations high in malnourished COPD patients6 but also that monocytes from those with weight loss produce a larger amount of cytokines spontaneously and in response to stimulation.’ Priming of human monocytes by hypoxia in vitro enhances cytokine release,8 and this sequence of events may occur in "tissue hypoxic" patients with emphysema. Consequently, emphysematous patients would become cachectic whereas bronchitic patients with relatively uncompromised tissue oxygenation would not.9 A similar explanation may well hold in patients with cachexia due to severe heart failure, who also have high concentrations of circulating TNF-a.’" The hypothesis that malnutrition in emphysema is merely a cytokine-mediated marker of chronic progressive tissue hypoxia would account for many of the features of emphysema-associated weight loss that have hitherto been difficult to explain-eg, the significance of weight loss as a poor prognostic sign even in patients with moderate airflow obstruction. Weight loss, being the result of a gas exchange abnormality (as shown by the close relation between muscle mass and diffusing capacity"), would be simply a reflection of worsening tissue oxygenation not worsening airflow obstruction. The onset of weight loss would thus signify advancing tissue hypoxia, which in due course would be incompatible with cellular function. The
stepped decline in weight and nutritional status that is seen in emphysematous patients against a background of a gradual decline in body weight probably results from a surge of inflammatory activity associated with infections and other stresses, occurring in the context of a lesser but nevertheless significant hypoxia-enhanced cytokine activity. The variable energy expenditure values noted in emphysema patients with similar degrees of respiratory impairment may be explained by variations in the level of cytokine activity at the time of study, TNF activity rather than lung dysfunction now being the primary determinant of energy expenditure. 12 The relative refractoriness of emphysema-associated malnutrition to nutritional supplementation can likewise be explained: however plentiful the supply of energy-providing substrate, lack of availability of tissue oxygen as an essential element in the energy-generating process will lead to suboptimal utilisation of the profferred nutrients." Since weight loss in emphysema and heart failure might well be the consequence of cytokine activity driven by tissue hypoxia, measures that merely attempt to improve nutritional status are unlikely to influence prognosis if the abnormalities underlying tissue hypoxia (alveolar destruction, pump failure) remain. Identification of cytokines as mediators of weight loss in these conditions raises the possibility that anti-TNF agents could be used to treat
the cachexia.
Mangalam K Sridhar Departments of Respiratory Medicine University of Glasgow, UK
and Human Nutrition,
1 Fowler JK, Goodlee R. Emphysema of the lungs. In: Diseases of the lungs. London: Longmans Green and Co, 1898: 171. 2 Wilson DO, Rogers RM, Wright EC, Anthonisen NR. Body weight in chronic obstructive pulmonary disease: the National Institutes of Health Intermittent Positive Pressure Breathing Trial. Am Rev Respir Dis 1989; 139: 1435-38. 3 Rogers RM, Donahoe M, Constanino J. Physiological effects of oral supplemental feeding in malnourished patients with chronic obstructive pulmonary disease. Am Rev Respir Dis 1992; 146: 1511-17. 4 Donahoe M, Rogers RM, Wilson DO, Pennock BE. Oxygen consumption of the respiratory muscles in normal and in malnourished patients with chronic obstructive pulmonary disease. Am Rev Respir Dis 1989; 140: 385-91. 5 Green JH, Muers MF. Comparisons between basal metabolic rate and diet induced thermogenesis in different types of chronic obstructive pulmonary disease. Clin Sci 1992; 83: 109-16. 6 Di Francia M, Barbier D, Mege J, Orehek J. Tumor necrosis factoralpha and weight loss in chronic obstructive pulmonary disease. Am JResp Crit Care Med 1994; 150: 1453-55. 7 de Gody I, Calhoun WJ, Donahoe M, Mancino J, Rogers RM. Cytokine production by peripheral blood monocytes of COPD patients. Am J Respir Crit Care Med 1994; 149: 1017 (abstr). 8 Bain M, Imrie M, Matusiewicz S, Greening AP. Hypoxia primes monocytes for an enhanced stimulated release of IL-6, IL-1 &bgr; and GM-CSF. Eur Respir J 1994; 7: 248 (abstr). 9 Filley G, Beckwitt H, Reeves J, Mitchell R. Chronic obstructive pulmonary disease: oxygen transport in two clinical types. Am J Med 1968; 44: 26-38. 10 Levine B, Kalman J, Mayer L, Fillit HM, Packer M. Elevated circulating levels of tumor necrosis factor in severe chronic heart failure. N Engl J Med 1990; 323: 236-41. 11 Engelen MPKJ, Schols AMWJ, Baken WC, Wesseling GJ, Wouters EFM. Nutritional depletion in relation to respiratory and peripheral skeletal muscle function in out-patients with COPD. Eur Respir J 1994; 7: 1793-97. 12 Elborn JS, Cordon SM, Western PJ, Macdonald IA, Shale DJ. Tumour necrosis factor-&agr;, resting energy expenditure and cachexia in cystic fibrosis. Clin Sci 1993; 85: 563-68. 13 Lehninger AL. Electron transport, oxidative phosphorylation, and regulation of ATP production. In: Principles of biochemistry. New York: Worth, 1982: 467-505.
CD44v6 and CD44v3 variants in inflammatory bowel disease See page 1205
Ulcerative colitis and Crohn’s disease are generally regarded as separate entities on the basis of their clinical and characteristics, presentations, histological radiographic and endoscopic features. Colonoscopy and the determination of anti-neutrophil cytoplasmic antibodies (ANCA) are specific and sensitive diagnostic procedures but there is no diagnostic gold standard. 1,2 A precise diagnosis has important implications for longterm outcome, especially with respect to colectomy. For example, the decision to carry out a rectum-sparing subtotal colectomy carries the risk of recurrence if the underlying condition is found to be Crohn’s disease. Yet in about 10% of patients undergoing colectomy for inflammatory bowel disease, especially in those requiring emergency surgery, histological evaluation does not allow confident distinction between ulcerative colitis and Crohn’s disease.3 Clinicians would therefore welcome a better diagnostic test. In this issue Rosenberg and colleagues describe the increased expression of CD44 isoforms v3 and v6 in ulcerative colitis and hold out the promise of distinguishing ulcerative colitis from Crohn’s disease and other forms of inflammatory bowel disease with this approach. Absence of CD44v6 expression from normal colonic mucosa has already been confirmed, but CD44v6 and CD44v3 have been identified in colorectal adenomas and cancer..J,5 Moreover, there are conflicting data on the distribution of these isoforms depending on the antibodies used.4 So as a diagnostic test these latest results seem promising but require confirmation. Study of the expression of isoforms of CD44 in the colon may also be important for understanding the pathophysiology and pathogenesis of ulcerative colitis. CD44 standard molecule is a widely distributed transmembranous glycoprotein that acts as a cell adhesion receptor. Its major ligand, hyaluronan, is a common component of extracellular matrices. CD44 ligation leads to various responses, including cell adhesion, cell migration, induction or at least support of differentiation, effects on other cell adhesion mechanisms, and interaction with cell activation signals. Downstream events following ligand binding by CD44 6 vary depending on the cell type and environment. Various isoforms of CD44 can be generated by alternative splicing of nuclear RNA. Isoforms show variations in the extracellular part of the molecule, which thereby enable the cells to contact other ligands in addition to, or instead of, hyaluronan. Alterations in cell behaviour and interactions can follow.’ The exact meaning of the appearance of variant isoforms of CD44 on the crypt epithelial cells in ulcerative colitis is unclear. The isoforms may be related to the aetiology of the disease and immune activation. Activation of T lymphocytes leads to upregulation of CD44v6. Appearance of the isoforms may also be related to lymphocyte homing and indicate that colonic epithelium is a target. There are other possibilities. Increased expression of CD44v6 and CD44v3 might indicate primary or secondary structural differences of the
epithelium (altered phenotype)
or
surrounding matrix,
or
1191
,
Apart from the scientific progress achieved already, tangible benefits for the London School have included laboratory renovations and the appointment of new staff. The three project supervisors in London each have their counterpart at Glaxo, and the scientist-to-scientist collaborations are deemed valuable. At this juncture sceptics might reasonably ask "what’s in this for the company?". Clearly short-term goals have been eschewed, but as a public relations exercise the initiative is unquestionably a success. Moreover, Glaxo has by this means secured an impressive array of medical research expertise to sharpen its competitive edge. Although not all academic researchers would feel comfortable with such an arrangement, as an example of an effective partnership between the pharmaceutical industry and academic health sciences it has much to offer. Medical science is not outwith the public domain but part of it, and medical scientists likewise have obligations to society at large. As Polanyi opined, scientists must participate in the public debate whereby all our futures are ultimately determined. Medical researchers are ideally placed to initiate that debate, to educate the public about the special attributes of the scientific method, and to use their
creativity wisely. The Lancet
COMMENTARY
Why do patients with emphysema lose weight? Weight loss has long been recognised as a feature of advanced emphysema.’ Data obtained from a trial of intermittent positive-pressure breathing in chronic obstructive pulmonary disease (COPD) sponsored by the National Institutes of Health showed that weight loss was a common complaint among such patients and that it was associated with considerably increased morbidity and mortality.2 The relation between mortality and low body weight was not only evident in patients with severe airflow obstruction; indeed it was strongest in those with less severe disease. Attempts to limit the adverse effects of malnutrition in COPD via nutritional supplementation programmes have had little success.3
Why do patients with COPD lose weight, and why is weight loss associated more with emphysema than with bronchitis? Moreover, how is weight loss linked to a poor outcome? Until lately the most favoured explanation was a mechanistic one-the increased work of breathing in emphysematous patients resulted in increased energy expenditure, negative energy balance, and weight loss/ However, patients with COPD who lose weight are not always hypermetabolic, while patients with similar increases in the work of breathing due to other respiratory diseases do not exhibit weight loss.5 Recent experimental work has focused on the role of cytokines in the 1190
pathogenesis of weight loss.6,7 Studies of TNF-a (cachexin) in COPD patients show that not only are serum concentrations high in malnourished COPD patients6 but also that monocytes from those with weight loss produce a larger amount of cytokines spontaneously and in response to stimulation.’ Priming of human monocytes by hypoxia in vitro enhances cytokine release,8 and this sequence of events may occur in "tissue hypoxic" patients with emphysema. Consequently, emphysematous patients would become cachectic whereas bronchitic patients with relatively uncompromised tissue oxygenation would not.9 A similar explanation may well hold in patients with cachexia due to severe heart failure, who also have high concentrations of circulating TNF-a.’" The hypothesis that malnutrition in emphysema is merely a cytokine-mediated marker of chronic progressive tissue hypoxia would account for many of the features of emphysema-associated weight loss that have hitherto been difficult to explain-eg, the significance of weight loss as a poor prognostic sign even in patients with moderate airflow obstruction. Weight loss, being the result of a gas exchange abnormality (as shown by the close relation between muscle mass and diffusing capacity"), would be simply a reflection of worsening tissue oxygenation not worsening airflow obstruction. The onset of weight loss would thus signify advancing tissue hypoxia, which in due course would be incompatible with cellular function. The
stepped decline in weight and nutritional status that is seen in emphysematous patients against a background of a gradual decline in body weight probably results from a surge of inflammatory activity associated with infections and other stresses, occurring in the context of a lesser but nevertheless significant hypoxia-enhanced cytokine activity. The variable energy expenditure values noted in emphysema patients with similar degrees of respiratory impairment may be explained by variations in the level of cytokine activity at the time of study, TNF activity rather than lung dysfunction now being the primary determinant of energy expenditure. 12 The relative refractoriness of emphysema-associated malnutrition to nutritional supplementation can likewise be explained: however plentiful the supply of energy-providing substrate, lack of availability of tissue oxygen as an essential element in the energy-generating process will lead to suboptimal utilisation of the profferred nutrients." Since weight loss in emphysema and heart failure might well be the consequence of cytokine activity driven by tissue hypoxia, measures that merely attempt to improve nutritional status are unlikely to influence prognosis if the abnormalities underlying tissue hypoxia (alveolar destruction, pump failure) remain. Identification of cytokines as mediators of weight loss in these conditions raises the possibility that anti-TNF agents could be used to treat
the cachexia.
Mangalam K Sridhar Departments of Respiratory Medicine University of Glasgow, UK
and Human Nutrition,
1 Fowler JK, Goodlee R. Emphysema of the lungs. In: Diseases of the lungs. London: Longmans Green and Co, 1898: 171. 2 Wilson DO, Rogers RM, Wright EC, Anthonisen NR. Body weight in chronic obstructive pulmonary disease: the National Institutes of Health Intermittent Positive Pressure Breathing Trial. Am Rev Respir Dis 1989; 139: 1435-38. 3 Rogers RM, Donahoe M, Constanino J. Physiological effects of oral supplemental feeding in malnourished patients with chronic obstructive pulmonary disease. Am Rev Respir Dis 1992; 146: 1511-17. 4 Donahoe M, Rogers RM, Wilson DO, Pennock BE. Oxygen consumption of the respiratory muscles in normal and in malnourished patients with chronic obstructive pulmonary disease. Am Rev Respir Dis 1989; 140: 385-91. 5 Green JH, Muers MF. Comparisons between basal metabolic rate and diet induced thermogenesis in different types of chronic obstructive pulmonary disease. Clin Sci 1992; 83: 109-16. 6 Di Francia M, Barbier D, Mege J, Orehek J. Tumor necrosis factoralpha and weight loss in chronic obstructive pulmonary disease. Am JResp Crit Care Med 1994; 150: 1453-55. 7 de Gody I, Calhoun WJ, Donahoe M, Mancino J, Rogers RM. Cytokine production by peripheral blood monocytes of COPD patients. Am J Respir Crit Care Med 1994; 149: 1017 (abstr). 8 Bain M, Imrie M, Matusiewicz S, Greening AP. Hypoxia primes monocytes for an enhanced stimulated release of IL-6, IL-1 &bgr; and GM-CSF. Eur Respir J 1994; 7: 248 (abstr). 9 Filley G, Beckwitt H, Reeves J, Mitchell R. Chronic obstructive pulmonary disease: oxygen transport in two clinical types. Am J Med 1968; 44: 26-38. 10 Levine B, Kalman J, Mayer L, Fillit HM, Packer M. Elevated circulating levels of tumor necrosis factor in severe chronic heart failure. N Engl J Med 1990; 323: 236-41. 11 Engelen MPKJ, Schols AMWJ, Baken WC, Wesseling GJ, Wouters EFM. Nutritional depletion in relation to respiratory and peripheral skeletal muscle function in out-patients with COPD. Eur Respir J 1994; 7: 1793-97. 12 Elborn JS, Cordon SM, Western PJ, Macdonald IA, Shale DJ. Tumour necrosis factor-&agr;, resting energy expenditure and cachexia in cystic fibrosis. Clin Sci 1993; 85: 563-68. 13 Lehninger AL. Electron transport, oxidative phosphorylation, and regulation of ATP production. In: Principles of biochemistry. New York: Worth, 1982: 467-505.
CD44v6 and CD44v3 variants in inflammatory bowel disease See page 1205
Ulcerative colitis and Crohn’s disease are generally regarded as separate entities on the basis of their clinical and characteristics, presentations, histological radiographic and endoscopic features. Colonoscopy and the determination of anti-neutrophil cytoplasmic antibodies (ANCA) are specific and sensitive diagnostic procedures but there is no diagnostic gold standard. 1,2 A precise diagnosis has important implications for longterm outcome, especially with respect to colectomy. For example, the decision to carry out a rectum-sparing subtotal colectomy carries the risk of recurrence if the underlying condition is found to be Crohn’s disease. Yet in about 10% of patients undergoing colectomy for inflammatory bowel disease, especially in those requiring emergency surgery, histological evaluation does not allow confident distinction between ulcerative colitis and Crohn’s disease.3 Clinicians would therefore welcome a better diagnostic test. In this issue Rosenberg and colleagues describe the increased expression of CD44 isoforms v3 and v6 in ulcerative colitis and hold out the promise of distinguishing ulcerative colitis from Crohn’s disease and other forms of inflammatory bowel disease with this approach. Absence of CD44v6 expression from normal colonic mucosa has already been confirmed, but CD44v6 and CD44v3 have been identified in colorectal adenomas and cancer..J,5 Moreover, there are conflicting data on the distribution of these isoforms depending on the antibodies used.4 So as a diagnostic test these latest results seem promising but require confirmation. Study of the expression of isoforms of CD44 in the colon may also be important for understanding the pathophysiology and pathogenesis of ulcerative colitis. CD44 standard molecule is a widely distributed transmembranous glycoprotein that acts as a cell adhesion receptor. Its major ligand, hyaluronan, is a common component of extracellular matrices. CD44 ligation leads to various responses, including cell adhesion, cell migration, induction or at least support of differentiation, effects on other cell adhesion mechanisms, and interaction with cell activation signals. Downstream events following ligand binding by CD44 6 vary depending on the cell type and environment. Various isoforms of CD44 can be generated by alternative splicing of nuclear RNA. Isoforms show variations in the extracellular part of the molecule, which thereby enable the cells to contact other ligands in addition to, or instead of, hyaluronan. Alterations in cell behaviour and interactions can follow.’ The exact meaning of the appearance of variant isoforms of CD44 on the crypt epithelial cells in ulcerative colitis is unclear. The isoforms may be related to the aetiology of the disease and immune activation. Activation of T lymphocytes leads to upregulation of CD44v6. Appearance of the isoforms may also be related to lymphocyte homing and indicate that colonic epithelium is a target. There are other possibilities. Increased expression of CD44v6 and CD44v3 might indicate primary or secondary structural differences of the
epithelium (altered phenotype)
or
surrounding matrix,
or
1191
,