Nutritional Therapy for Cancer Cachexia Cancer

COMMENTARIES 1391

Colon clinical situations ranging from surgery9 ...... 10 to adult respiratory distress syndrome. Gut: first published as 10.1136/gut.52.10.1394 on 11 September 2003. Downloaded from Fearon’s group have pioneered the use of fish oil in the treatment of pancreatic Nutritional therapy for cancer cachexia cancer. The results of a number of small trials have been reported in which R F Grimble the oil, or the main n-3 PUFA that it contains (eicosapentaenoic acid ...... (EPA)), has been demonstrated to In cancers where high inflammatory stress is usual, protein rich reduce the high rates of weight loss in such patients.11 12 supplements containing n-3 polyunsaturated fatty acids and high As a logical extension to this work, an levels of antioxidant vitamins can reverse severe weight loss international, multicentre, double blind, randomised trial13 is reported in this he process of inflammation has a and protein loss. Losses of up to 75% of issue of Gut [see pages 1479–86]. The paradoxical effect. This is mostly body stores can occur.3 Furthermore study examined the effects of an n-3 Tdue to the metabolic responses visceral protein mass is relatively pre- PUFA and antioxidant enriched oral triggered by the release of the three served. While the desire to eat is strong supplement on loss of weight and lean proinflammatory cytokines, interleukin in starvation, in cachexia severe anor- tissue loss in pancreatic cancer patients. 1b (IL-1b), tumour necrosis factor a exia occurs. The precise mechanism for In the study, 95 patients received the (TNF-a), and interleukin 6 (IL-6). As an the appetite loss in cachexia is unclear. enriched supplement and 105 received integral part of the body’s response to However, proinflammatory cytokines, the control diet. The former diet con- infection and injury, these mediators raised serotoninergic activity in the tained an amount of n-3 PUFA equiva- release substrate, from host tissues, to hypothalamus, and leptin have been lent to 6 g fish oil per day, and vitamin support T and B lymphocyte activity, implicated.3 Chemotherapy unfortu- C and E at over four and eight times the create a hostile environment for invad- nately imposes oxidant stress on the recommended amount for healthy sub- ing pathogens, via a raised body tem- patient, thereby providing a further jects, respectively. This level of antiox- perature and oxidant production, and boost to the inflammatory process.4 idant vitamin supplementation was initiate downregulation of the process A number of approaches have been similar to that used by Pacht and once invasion has been defeated.1 All of taken to improve nutritional status in colleagues10 who successfully used a these metabolic effects come at consid- cancer patients. Attempts to raise energy combination of n-3 PUFA and antiox- erable cost to the host, as witnessed by and protein intake by counselling have idant, in an enteral formulation, to the extensive tissue depletion, anorexia, been successful, but despite improve- reducing severe lung inflammation in and anaemia seen in severely infected ments over a three month period, no adult respiratory distress syndrome and injured patients.2 However, the cost improvement in weight, anthropometric patients. is of great biological value if recovery measures, response rate, survival, or The large number of patients in the from infection and injury are achieved. quality of life have been demon- multicentre study13 permitted subgroup The inflammatory process contains ele- strated.56 Disappointing results were analysis to determine whether the dose http://gut.bmj.com/ ments which inherently upregulate the also obtained when nutrient intake of supplement exerted an effect. Some response. Oxidants will increase pro- was increased by the parenteral route. interesting insights were achieved by inflammatory cytokine production by The deleterious effects of parenteral this strategy. There was a linear rela- activating nuclear factor kB (NFkB). A nutrition (for example, increased infec- tionship between change in lean body wide range of genes associated with tive complications) led the American weight and enrichment of plasma phos- the inflammatory process have NFkB College of Physicians, in a position pholipids with EPA, indicating that

response elements in their structure. paper, to conclude ‘‘parenteral nutri- the greater the intake of n-3 PUFA, the on September 29, 2021 by guest. Protected copyright. These include genes for proinflamma- tional support was associated with net greater the protein accretion in the tory cytokines and adhesion molecules.1 harm, and no conditions could be patients. Furthermore, when body Tumour cells may initiate the inflam- defined in which such treatment weight change was related to dietary matory response as effectively as invad- appeared to be of benefit’’.3 protein intake, only those patients con- ing pathogens. However, while the While the precise mechanism(s) of suming the n-3 PUFA enriched formu- inflammatory process may be effective cachexia is unclear it is self evident that lation showed a positive relationship. In in dealing with single malignant cells, the inflammatory process is exceedingly other words, a synergistic effect was once cancer is established the inflam- strong in weight losing cancer patients. obtained by consumption of protein matory process becomes a cause of the Thus the patient’s nutrient intake is in the presence of n-3 PUFA. patient’s demise, rather than a means of dissipated by the hypermetabolism Disappointingly, the authors do not destroying the tumour. In addition to induced by the inflammatory state. mention any indices of inflammation stimulating the cytokine mediated and Thus nutritional therapy, to improve (for example, plasma IL-6, C reactive hormonal aspects of the inflammatory survival in cancer patients, must make protein) in their paper. It is not there- response, tumour specific products also the inflammatory process its prime fore possible to judge whether a con- add to the level of inflammatory stress target.7 Among nutrients that may be comitant reduction in inflammatory in the patient. effective in this respect are n-3 or stress occurred during the time that n-3 The tissue depletion that occurs dur- omega-3, polyunsaturated fatty acids PUFA was facilitating accretion of lean ing inflammation is different qualita- (n-3PUFA) and antioxidants. The for- body mass. tively to that seen during starvation and mer have been shown to be particularly In the clinical setting, n-3 PUFA are forms part of the syndrome of cancer effective anti-inflammatory agents in often given in immunonutrient mix- cachexia. While starvation results pri- rheumatoid arthritis.8 Moreover, the tures (as in the present study13) and marily in fat loss, with secondary loss in effectiveness of n-3 PUFA in modulating thus it is difficult to determine whether muscle and visceral protein mass, the inflammatory process has been the n-3 PUFA per se are achieving the cachexia results almost equally in fat demonstrated in a diverse range of observed effect or whether there is some

www.gutjnl.com 1392 COMMENTARIES synergistic interaction within the body protein rich supplements containing n- 10 Pacht ER, DeMichele SJ, Nelson JL, et al. Enteral nutrition with eicosapentaenoic acid,

between the components of the clinical Gut: first published as 10.1136/gut.52.10.1394 on 11 September 2003. Downloaded from 3 PUFA and high levels of antioxidant gamma-linolenic acid, and antioxidants feed. It is likely that oxidant/antioxidant vitamins, can reverse severe weight loss. reduces alveolar inflammatory mediators and status had a part to play in the response It remains to be seen whether this effect protein influx in patients with acute respiratory observed in the multicentre study.13 is achieved by an anti-inflammatory distress syndrome. Crit Care Med 2003;31:491–500. Experimental studies have shown that mechanism and whether cancers in 11 Barber MD, Ross JA, Preston T, et al. antioxidants can decrease NFkkB acti- which cachexia is not as severe as in Fish oil-enriched nutritional supplement vation and reduce muscle protein loss in pancreatic cancer will respond favour- attenuates progression of the acute-phase animal cachexia models and during cell response in weight-losing patients with ably to similar nutritional therapy. advanced pancreatic cancer. J Nutr culture.14–16 Indeed, in a randomised Gut 2003;52:1391–1392 1999;129:1120–5. double blind study on weight losing 12 Wigmore SJ, Barber MD, Ross JA, et al. Effect of acquired immunodeficiency syndrome Correspondence to: Professor R F Grimble, oral eicosapentaenoic acid on weight loss in Institute of Human Nutrition, School of patients with pancreatic cancer. Nutr Cancer patients, an antioxidant-glutamine sup- 2000;36:177–84. plement increased body cell mass.17 It Medicine, University of Southampton, Southampton SO16 7PX, UK; [email protected] 13 Fearon KCH, von Meyenfeldt MF, Moses AGW, should be noted that glutamine, by et al. Effect of a protein and energy dense n-3 acting as a source of glutamate, may fatty acid enriched oral supplement on loss of weight and lean tissue in cancer cachexia: a provide one of the three amino acids REFERENCES randomised double blind trial. Gut (glycine, cysteine, glutamate) required 1 Grimble RF. Stress proteins in disease: 2003;52:1479–86. for the synthesis of the key antioxidant metabolism on a knife edge. Clin Nutr 14 Sen CK, Khanna S, Reznick AZ, et al. glutathioine (GSH). Denno et al noted, 2001;20:469–76. Glutathione regulation of tumor necrosis 2 Grimble RF. Malnutrition and the immune factor-alpha-induced NF-kappa B activation in a rat model, that glutamine adminis- response. 2. Impact of nutrients on cytokine in skeletal muscle-derived L6 cells. tered parenterally enhanced plasma and biology in infection. Trans R Soc Trop Med Hyg Biochem Biophys Res Commun hepatic GSH concentrations.18 Cysteine 1994;88:615–19. 1997;237:645–9. acts as the rate limiting amino acid in 3 Barber MD, Ross JA, Fearon KC. Cancer 15 Buck M, Chojkier M. Muscle wasting and cachexia. Surg Oncol 1999;8:133–41. dedifferentiation induced by oxidative GSH synthesis and studies in rat models 4 Kovacic P, Osuna JA jr. Mechanisms of anti- stress in a murine model of cachexia is show that, during low protein intakes, cancer agents: emphasis on oxidative stress and prevented by inhibitors of nitric oxide addition of the amino acid restores GSH electron transfer. Curr Pharm Des synthesis and antioxidants. EMBO J 1996;15:1753–65. to normal levels following injection with 2000;6:277–309. 5 Evans WK, Nixon DW, Daly JM, et al. A 16 Hyun Y, Ishiko O, Honda K, et al. Probucol 19 TNF-a or endotoxin. In the multicentre randomised trial of oral nutritional support decreases total body fat loss in VX2-carcinoma- study,13 accretion of lean body mass in versus ad lib nutritional intake during chemo induced cachectic rabbits. Oncol Rep patients receiving fish oil was positively therapy for advanced colorectal and non-small- 2001;8:1309–11. cell lung cancer. J Clin Oncol 1987;5:113–24. 17 Shabert JK, Winslow C, Lacey JM, et al. related to protein intake. While the 6 Ovesen L, Allingstrup L, Hannibal J, et al. Effect of Glutamine-antioxidant supplementation amino acid composition of protein in dietary counseling on food intake, body weight, increases body cell mass in AIDS patients the supplement is not quoted in the response rate, survival, and quality of life in with weight loss: a randomized, double- paper, it is feasible that it may have cancer patients undergoing chemotherapy: a blind controlled trial. Nutrition prospective, randomised study. J Clin Oncol 1999;15:860–4. indirectly improved antioxidant status 1993; 11:2043–9. 18 Denno R, Rounds JD, Faris R, et al. Glutamine- by providing the three necessary amino 7 Grimble RF. Nutritional modulation of immune enriched total parenteral nutrition enhances function. Proc Nutr Soc 2001;60:389–97. plasma glutathione in the resting state. J Surg Res acids for GSH synthesis, thereby indi- http://gut.bmj.com/ 8 Calder PC. Dietary modification of inflammation 1996;61:35–8. rectly reducing inflammatory stress in with lipids. Proc Nutr Soc 2002;61:345–58. 19 Hunter EA, Grimble RF. Dietary sulphur the patients. 9 Gianotti L, Braga M, Fortis C, et al. A prospective, amino acid adequacy influences glutathione While there are a number of unan- randomized clinical trial on perioperative feeding synthesis and glutathione-dependent swered questions posed by the study it with an arginine-, omega-3 fatty acid-, and RNA- enzymes during the inflammatory response enriched enteral diet: effect on host response and to endotoxin and tumour necrosis does illustrate that in cancers where nutritional status. JPEN J Parenter Enteral Nutr factor-alpha in rats. Clin Sci (Lond) high inflammatory stress is usual, 1999;23:314–20. 1997;92:297–305. on September 29, 2021 by guest. Protected copyright.

Liver disturbances. These studies have also ...... established the pathogenic role of circulatory dysfunction in organ specific syndromes that commonly develop in Origins of cardiac dysfunction in cirrhotic patients, such as the hepatorenal and the hepatopulmonary syndromes.23 cirrhosis The heart is another functionally com- promised organ in cirrhotic patients. W Jime´nez, V Arroyo However, whether the hyperdynamic circulation, by overloading the heart, ...... induces cirrhotic cardiomyopathy or Is cirrhotic cardiomyopathy a specific cardiac dysfunction of whether this is a specific cardiac dysfunction of cirrhotic patients has been cirrhotic patients or is it induced by the hyperdynamic circulation subject of extensive discussions.4 in these patients? Cardiac function abnormalities in cirrhosis are clinically not apparent. he clinical course of patients with and decreased systemic vascular resis- However, when cardiac function is advanced liver disease is compli- tance.1 Clinical and experimental inves- explored, a reduction in right ventricular Tcated by progressive impairment in tigations performed during the past two volume, probably secondary to reduced circulatory function characterised by decades have shed light on the mul venous return, and left ventricular dys- low arterial pressure, high cardiac output, tiple mechanisms accounting for these function, characterised by left ventricular

www.gutjnl.com COMMENTARIES 1393 preload and volume, are observed.56 tendency to prolong QT intervals. This is BNP were related to septal thickness

Moreover, cardiac structural abnormal- in agreement with the results of Bernardi and left ventricular diameter at the end Gut: first published as 10.1136/gut.52.10.1394 on 11 September 2003. Downloaded from ities, including hypertrophy of the myo- and colleagues22 showing a prolonged of diastole.31 cardium and increased left ventricle QT interval and other electrophysiologi- In fact, although some authors con- thickness and hence diastolic dysfunc- cal abnormalities in cardiac excitation sidered cirrhotic cardiomyopathy, at tion, have also been described.7 Cirrhotic and repolarisation in cirrhotic patients. best, a complication of alcoholic liver cardiomyopathy is latent, probably Exposure of cardiac myocytes for long disease and, at worst, a non-existent because of the low peripheral vascular periods of time to endogenous sub- medical invention, numerous evidence resistance presented by these patients, stances with cardiac function inhibi- supports the concept of a specific cardiac which reduces cardiac afterload. The tory properties should also be taken disorder peculiar to cirrhosis. What is existence of an abnormal ventricular into consideration. There is a wide still an unanswered question is whether behaviour can however be unveiled array of cardiodepressant factors such this abnormality results from the hyper- during exercise or following pharmaco- as nitric oxide, endotoxins, endothelins, dynamic circulation also present in logical stress. It has been demonstrated bile acids, and cytokines, that have these patients. In the current of Gut that left ventricular end diastolic pres- been demonstrated to be increased in issue, Herikssen and colleagues32 use an sure increases and stroke index and left cirrhotic patients and experimental elegant experimental approach to solve 12324 ventricular ejection fraction decrease models of portal hypertension. this dilemma [see pages 1511–7]. more in cirrhotic patients than in con- Recently, brain natriuretic peptide These investigators have simultaneously trol subjects.8–10 (BNP), a cardiac hormone belonging to assessed plasma levels of BNP and total Impaired left ventricular performance the natriuretic isopeptide family, has proBNP, and indicative parameters of in cirrhotic patients was initially attracted increasing attention as an liver and cardiac dysfunction and hyper- thought to be due to the so-called accurate marker of left ventricular dys- dynamic circulation in a large group of alcoholic heart muscle disease, also function. In fact, BNP is an independent cirrhotic patients. ProBNP is the high known as alcoholic cardiomyopathy,11 predictor of high left ventricular pres- molecular precursor of functionally because almost all earlier studies were sure,25 estimates left ventricular systolic active BNP. Cleavage of proBNP is performed in alcoholic patients. dysfunction, and closely correlates with mainly located in the myocyte and However, clear dissimilarities between the New York Heart Association results in secretion to the systemic alcoholic and cirrhotic cardiomyopathy (NYHA) classification.26 The accuracy circulation of equimolar amounts of exist. Firstly, depressed ventricular of BNP for the detection of left ventri- the N terminal fragment of proBNP responsiveness has been observed in cular systolic dysfunction is similar to (NT-proBNP) and BNP. NT-proBNP humans and rats with cirrhosis of non- that of prostate specific antigen for the circulates at considerable concentrations alcoholic aetiology.12 13 On the other detection of prostate cancer, and is in human plasma, is stable in human hand, alcoholic heart muscle disease is superior to that of mammography for blood, and is less dependent on pulsatile secondary to impaired contractile pro- breast carcinoma and Papanicolau fluctuations, produced by postural tein synthesis and formation of immu- smears for cervical cancer.27 BNP is changes or other physiological nogenic cardiac protein acetaldehyde released from cardiac ventricles in responses, than BNP. Total proBNP adducts14 whereas clearly differentiated response to ventricular volume expan- measurement is performed after in vitro mechanisms are involved in the patho- sion and pressure overload, suggesting plasma trypsinisation and it has been http://gut.bmj.com/ genesis of cirrhotic cardiomyopathy. that BNP levels are a more sensitive and suggested that this is a more reliable Several studies have shown sympa- specific indicator of ventricular disor- method to assess BNP secretion as it thetic and parasympathetic autonomic ders than other natriuretic peptides. does not depend on precursor proces- dysfunction in cirrhotic patients.15 Data from heart failure investigations sing.33 Confirming previous investiga- Hypotheses have been raised suggesting suggest that the increased release of tions, cirrhotic patients showed that the origin of this abnormality could BNP is a compensatory response elicited increased circulating levels of BNP, be located in the nervous system due to by ventricular remodelling aimed at which paralleled the results obtained on September 29, 2021 by guest. Protected copyright. damage of the peripheral nerves or reducing systemic pressure load hyper- on analysing total proBNP. The most because of changes in endogenous trophy through sodium and water diur- interesting finding of this study is that neurotransmitters.816 Impaired b adre- esis. Thus BNP has become a specific ventricular natriuretic peptide secretion nergic signal transduction may also be marker of ventricular damage rather closely correlates with indicative para- an important element in the pathogen- than just an indicator of volume over- meters of abnormal liver (Child score, esis of cirrhotic cardiomyopathy. load.28 hepatic venous pressure gradient, and Experimental studies have shown Cardiac natriuretic peptides, namely serum albumin) and cardiac function decreased b adrenergic receptor density atrial natriuretic peptide and BNP, have (plasma volume, heart rate, and QT and receptor desensitisation in cardio- long been known to be elevated in interval) but not with those character- 17 cytes of cirrhotic rats. In addition, cirrhotic patients as a consequence of istic of the hyperdynamic circulation (cardiac output and systemic vascular leucocytes of cirrhotic patients also increased cardiac release and not resistance). Therefore, these results ser- present decreased abundance of b adre- because of impaired hepatic extrac- noreceptor.18 Heart receptor and post iously jeopardise the concept that tion.29 30 However, they have been gen- receptor defects are supported by the increased BNP levels in cirrhotic erally regarded as markers of volume demonstration of reduced function and patients are due to the hyperdynamic expression of cardiac G proteins in overload rather than markers of cardiac circulation. Rather, they support the fact cirrhotic animals17 and impaired cardiac dysfunction. Recently, Wong and col- that increased secretion of this natriure- 31 excitation-contraction coupling in portal leagues proposed that BNP could be an tic peptide is a consequence of ventri- hypertensive rats.19 Plasma membrane indicator of cirrhotic cardiomyopathy. cular dysfunction, which seems to fluidity and ion channel function are These authors measured cardiac natri- progress in parallel with the severity of impaired in cirrhosis.20 Recently, Ward uretic peptide levels and cardiac struc- the liver disease. These findings should and colleagues21 described a decrease in tural parameters in a group of 36 also stimulate further research to clearly K+ current in ventricular myocytes of cirrhotic patients with and without delineate the molecular and cellular cirrhotic rats, which would result in a ascites. Increased circulating levels of mechanisms responsible for the structural

www.gutjnl.com 1394 COMMENTARIES and functional abnormalities distinc- alcoholic cirrhosis of the liver. Am J Cardiol relationship with severity and aetiology of the 1984;54:852–5. disease and possible pathogenic factors. tive of cirrhotic cardiomyopathy. 9 Moller S, Henriksen JH. Cirrhotic Hepatology 1998;27:28–34. Gut: first published as 10.1136/gut.52.10.1394 on 11 September 2003. Downloaded from Identification of well defined therapeutic cardiomyopathy: a pathophysiological review of 23 Jimeńez W, Poo JL, Leivas A. Endothelin and targets will certainly improve life qual- circulatory dysfunction in liver disease. Heart systemic, renal and hepatic hemodynamic ity and expectations of patients with 2002;87:9–15. disturbances in cirrhosis. In: Arroyo V, Gine`s P, 10 Ma Z, Lee SS. Cirrhotic cardiomyopathy: Getting Rode´s J, eds. Ascites and renal dysfunction advanced liver disease. to the heart of the matter. Hepatology in liver disease. Pathogenesis diagnosis and 1996;24:451–9. Gut 2003;52:1392–1394 treatment. London: Blackwell Science, 11 Fernandez-Sola J, Estruch R, Grau JM, et al. The 1999:291–303. relation of alcoholic myopathy to 24 Ros J, Jimenez W, Lamas S, et al. Nitric oxide ...... cardiomyopathy. Ann Intern Med production in arterial vessels of cirrhotic rats. Authors’ affiliations 1994;120:529–36. Hepatology 1995;21:554–60. 12 Grose RD, Nolan J, Dillon JF, et al. Exercise- 25 Maeda K, Tsutamoto T, Wada A, et al. Plasma W Jimeńez, Hormonal Laboratory, Hospital induced left ventricular dysfunction in alcoholic Clinic, University of Barcelona, Spain brain natriuretic peptide as a biochemical and non-alcoholic cirrhosis. J Hepatol marker of high left ventricular end-diastolic V Arroyo, Liver Unit, Hospital Clinic, 1995;22:326–32. pressure in patients with symptomatic left University of Barcelona, Spain 13 Ingles AC, Hernandez I, Garcia-Estan J, et al. ventricular dysfunction. Am Heart J Limited cardiac preload reserve in conscious 1998;135:825–32. cirrhotic rats. Am J Physiol 1991;260:1912–17. Correspondence to: Dr W Jimeńez, Hormonal 26 Clerico A, Iervasi G, Del Chicca MG, et al. 14 Harcombe AA, Ramsay L, Kenna JG, et al. Circulating levels of cardiac natriuretic peptides Laboratory, Hospital Clıńic i Provincial, Circulating antibodies to cardiac protein- (ANP and BNP) measured by highly sensitive and Villarroel 170, 08036 Barcelona, Spain; acetaldehyde adducts in alcoholic heart muscle specific immunoradiometric assays in normal [email protected] disease. Clin Sci 1995;88:263–8. subjects and in patients with different degrees of 15 Trevisani F, Sica G, Mainqua P, et al. Autonomic heart failure. J Endocrine Invest dysfunction and hyperdynamic circulation in 1998;21:170–9. cirrhosis with ascites. Hepatology REFERENCES 27 McDonagh TA, Robb SD, Murdoch DR, et al. 1999;30:1387–92. Biochemical detection of left-ventricular systolic 1 Arroyo V, Jimeńez W. Renal and circulatory 16 Chaudhry V, Corse AM, O’Brian R, et al. dysfunction. Lancet 1998;351:9–13. dysfunction in cirrhosis. Lights and shadows in an Autonomic and peripheral (sensorimotor) 28 Dhingra H, Roongsritong C, Kurtzman NA. Brain important clinical problem. J Hepatology neuropathy in chronic liver disease: a clinical and 2000;32(suppl 1):157–70. electrophysiological study. Hepatology natriuretic peptide: role in cardiovascular and 2 Arroyo V, Guevara M, Gines P. Hepatorenal 1999;29:1698–703. volume homeostasis. Semin Nephrol syndrome in cirrhosis: pathogenesis and 17 Ma Z, Miyamoto A, Lee SS. Role of altered b- 2002;22:423–37. treatment. Gastroenterology adrenoreceptor signal transduction in the 29 Gines P, Jimenez W, Arroyo V, et al. Atrial 2002;122:1658–76. pathogenesis of cirrhotic cardiomyopathy in rats. natriuretic factor in cirrhosis with ascites: 3 Mu¨ller C, Schenk P. Hepatopulmonary syndrome. Gastroenterology 1996;110:1191–8. plasma levels, cardiac release and splanchnic Wien Klin Wochenschr 1999;111:339–47. 18 Gerbes AL, Remien J, Ju¨ngst D, et al. Evidence for extraction. Hepatology 1988;8:636–42. 30 La Villa G, Romanelli RG, Casini Raggi V, et al. 4 Blendis L, Wong F. Is there a cirrhotic down regulation of b2-adrenoceptors in cirrhotic cardiomyopathy? Am J Gastroenterology patients with severe ascites. Lancet Plasma levels of brain natriuretic peptide in 2000;11:3026–8. 1986;1:1409–11. patients with cirrhosis. Hepatology 5 Moller S, Sendergaard L, Mogelvang J, et al. 19 Zavecz JH, Bueno O, Maloney RE, et al. Cardiac 1992;16:156–61. Decreased right heart blood volume determined excitation-contraction coupling in the portal 31 Wong F, Siu S, Liu P, et al. Brain natriuretic by magnetic resonance imaging: Evidence of hypertensive rat. Am J Physiol peptide: is it a predictor of cardiomyopathy in central underfilling in cirrhosis. Hepatology 2000;279:G28–39. cirrhosis. Clin Sci 2001;101:621–8. 1995;22:472–8. 20 Moreau R, Komaichi H, Kirstetter P, et al. Altered 32 Henriksen JH, Gøtze JP, Fuglsang S, et al. 6 Laffi G, Barletta G, La Villa G, et al. Altered control of vascular tone by adenosine Increased circulating pro-brain natriuretic cardiovascular responsiveness to active tilting in triphosphate-sensitive potassium channels in rats peptide (proBNP) and brain natriuretic peptide nonalcoholic cirrhosis. Gastroenterology with cirrhosis. Gastroenterology (BNP) in patients with cirrhosis: relation to

1997;113:891–8. 1994;106:1016–23. cardiovascular dysfunction and severity of http://gut.bmj.com/ 7 Pozzi M, Carugo S, Boari G, et al. Evidence of 21 Ward CA, Ma Z, Lee SS. Potassium currents in disease. Gut 2003;52:1511–7. functional and structural cardiac abnormalities in atrial and ventricular myocytes from a rat model 33 Goetze JP, Kastrup J, Pedersen F, et al. cirrhotic patients with and without ascites. of cirrhosis. Am J Physiol 1997;273: Quantification of pro-B-type natriuretic peptide Hepatology 1997;26:1131–7. G537–44. and its products in human plasma by an analysis 8 Kelbaek H, Eriksen J, Brynjolf I, et al. Cardiac 22 Bernardi M, Calandra S, Colantoni A, et al. Q-T independent precursor processing. Clin Chem performance in patients with asymptomatic interval prolongations in cirrhosis: prevalence, 2002;48:1035–42. on September 29, 2021 by guest. Protected copyright.

Inflammatory bowel disease environmental, infectious, and immu- ...... nological factors. All of these different aetiological aspects are reconciled in a paradigm, in which CD could result Transplanting the genetic susceptibility from disturbances of the intestinal barrier and pathological activation of to Crohn’s disease the intestinal immune response towards M H Holtmann, M F Neurath luminal bacterial antigens in individuals with genetic susceptibility...... Immunological key players for the pathogenesis of CD have been identi- Susceptibility to Crohn’s disease may be transferred via fied, including cellular components such haematopoietic stem cells, highlighting the pivotal role of genetic as lamina propria macrophages and factors in the pathogenesis of Crohn’s disease CD4+ T lymphocytes as well as cytokines such as tumour necrosis factor a (TNF- a), interleukin (IL)-6, IL-12, IL-18, and rohn’s disease (CD) is one of the are affected, with a peak incidence others.1–3 Identification of these patho- two most common forms of between 15 and 35 years.1 The aetiology genetically relevant factors has been Cinflammatory bowel disease of IBD is still unclear and should be greatly facilitated by the availability of (IBD). The prevalence of CD has considered as multifactorial according appropriate animal models, in particular increased in Western countries over the to recent studies.2 Genetic factors seem genetically engineered knockout mice or past decades and mainly young patients to play a pathogenic role as well as transgenic mice, respectively. When

www.gutjnl.com COMMENTARIES 1395

SCID mice lacking functional B cells and susceptibility to CD. Finally, certain HLA The 8.1 HLA haplotype previously asso-

T cells are reconstituted with a special haplotypes located at IBD3 have been ciated with CD was not found. Gut: first published as 10.1136/gut.52.10.1394 on 11 September 2003. Downloaded from subset of CD4+ T helper cells expressing suggested to confer a slightly increased The authors conclude correctly that the surface markers CD45Rbhigh or overall risk for the development of CD. the findings of the HLA class mis- CD62L, they develop chronic colitis.4 The recent cloning of the NOD2/ matches at IBD3 and the CD associated These T helper cell subsets are thought CARD15 gene on the gene locus IBD1 polymorphism of the 59 UTR of NOD2/ to differentiate preferentially towards and the identification of a large number CARD15 do not prove that these genetic Th1 cells in the host producing those of different NOD2 mutations in a sub- variations are the underlying cause for proinflammatory cytokines that are group of patients with CD13 14 has raised an adoptive transfer of genetic suscept- involved in the pathogenesis of CD, new interest in genetics in CD. Most ibility to CD from donor to recipient via such as TNF-a.56 To date, however, mutations are localised in a structurally ASCT. Nevertheless, their findings make clinical and experimental evidence for characteristic C terminal domain of the the idea likely. This case thus nicely the role of distinct mononuclear cell NOD2 protein that resembles bacterial illustrates the meaning of the multi- populations has been limited. There are lipopolysaccharide binding toll-like factorial pathogenesis of CD. The pre- some reports on long term remission of receptors. In vitro studies showed that sence of genetic susceptibility factors by CD after bone marrow transplantation.7 NOD2/CARD15 activates the transcrip- itself is not sufficient to elicit clinical CD Furthermore, human immunodeficiency tion factor nuclear factor kB. There is as the donor never had symptoms of virus (HIV) associated decrease in CD4+ evidence that NOD2/CARD15 is colitis. Development of clinical CD T helper cell number seems to induce expressed in monocytes and intestinal requires the coincidence of genetic clinical remission of CD.8 In addition, it epithelial cells. As a potential intracel- susceptibility and a special microenvir- has recently been shown that the lular receptor for bacterial components, onment in the gut, depending on immunosuppressive drug of choice for NOD2/CARD15 may be involved in the alterations of the intestinal epithelium the long term treatment of CD, early innate immune response (includ- and/or the intestinal flora. It may be azathioprine, promotes apoptotic cell ing defensin production) that induces speculated whether conditioning che- death of lamina propria CD4+ T helper the physiological state of tolerance motherapy, including fludarabine and cells and one effect of the anti-TNF towards bacterial antigens from the melphalan, altered the intestinal epithe- antibody Infliximab is the rapid induc- gut lumen.15 This concept might help lium or whether the long term antibiotic tion of apoptosis of peripheral blood to explain why inactivation of NOD2/ and immunosuppressive therapy post monocytes and lamina propria T cells.910 CARD15 increases susceptibility to CD. ASCT might have altered the patient’s In their case report in this issue of Finally, NOD2/CARD15 mutations in CD intestinal microenvironment such that Gut, Sonwalkar and colleagues11 report correlate with the development of ileal colitis could develop from susceptibility on a patient with Hodgkin’s lymphoma and fibrostenotic forms of CD.16 factors carried over from the stem cell who developed fulminant colitis follow- To support the idea that susceptibility donor to the recipient. ing non-myeloablative allogeneic stem for CD has been transferred by ASCT, Starting from the present case of a cell transplantation (ASCT) [see pages the authors performed a detailed genetic probable adoptive transfer of CD, the 1518–21]. Although the clinical course analysis of the CD susceptibility loci in authors discuss whether ASCT donor with sudden onset of severe bloody the patient who developed CD after selection should include screening for diarrhoea and pancolitis sparing the ASCT and in the donor.11 This included IBD. They suggest that formal question- http://gut.bmj.com/ terminal ileum were atypical, the colitis the NOD2/CARD15 gene on the IBD1 ing about IBD should be included was classified as Crohn’s colitis based on locus, including the 59 UTR (chromo- during ASCT donor ascertainment. the histological findings of patchy trans- some 16) HLA haplotypes on the IBD3 However, given the current paradigm mural inflammation and the presence of locus (chromosome 6), with special of IBD having a multifactorial genesis,17 non-caseating epitheloid granuloma. In focus on non-classical HLA class III gene what consequence would such a screen- addition, thorough diagnostic testing haplotypes and three single nucleotide ing have? In light of the efforts neces-

ruled out tuberculosis, graft versus host polymorphisms at the IBD5 locus. sary, using word wide data bases to on September 29, 2021 by guest. Protected copyright. disease, neutropenic colitis, vasculitis, Although the screening was negative identify appropriate HLA matched HIV, herpes simplex virus, or cytomega- for all 30 NOD2/CARD15 mutations donors for ASCT in a timely manner, lovirus colitis as potential differential described, there was a change in a 59 would one really decline a potential diagnoses. This report is remarkable in UTR polymorphism of the NOD2/ donor only because of a family history so far as it strongly suggests—without CARD15 gene at position 233 between of IBD? Given the weak correlation of proving definitely—for the first time donor and recipient. The donor and most IBD linked genes with clinical directly in the human system that sus- post ASCT recipient were homozygous development of the disease, should ceptibility to CD can be transferred via for a T allele that may be associated with volunteers be kept from stem cell dona- haematopoietic stem cells. This report CD, while the pre ASCT recipient was tion because of genetic susceptibility for might thus be considered as a proof of homozygous for the wild-type G allele. IBD? Larger studies are warranted, principle for the pivotal role of genetic High resolution molecular typing con- including formal questioning about factors in the pathogenesis of CD. firmed that donor and pre ASCT reci- IBD in the family history of stem cell An aetiological role of genetic factors pient DNAs were matched for most of donors and recipients as proposed by the has long been discussed based on family the HLA class I and II haplotypes except authors, complemented by molecular and ethnic studies. The first molecular for HLA-DPB1 and HLA-B where a novel screening for relevant gene loci such as genetic evidence was provided by large allelic variant was identified in the NOD2 and prospective follow up of linkage analyses by microsatellites, sug- recipient. However, genotyping for 320 these patients. This way, empiric data gesting relevant genetic loci on chromo- single nucleotide polymorphisms in 24 might be generated to address this some 5 (IBD5), chromosome 6 (IBD3), non-classical HLA class III genes at particular question. and chromosome 16 (IBD1).12 The IBD5 IBD3 between HLA-E and TAPBP However, the issue raised by the locus comprises a cluster of genes cod- revealed significant mismatches at authors should be put into a broader ing for cytokine genes involved in Th1/ several sites, including MICB, TNF, perspective. The molecular approach in Th2 differentiation, and single nucleo- HSP70, NOTCH4, and LMP2 and a medical research has led to the identi- tide polymorphisms are associated with double haplotype mismatch at LMP7. fication of numerous genes as potentially

www.gutjnl.com 1396 COMMENTARIES relevant for disease and their number is Mainz, Germany; 9 ten Hove T, van Montfrans C, Peppelenbosch MP, [email protected] et al. Infliximab treatment induces apoptosis of increasing rapidly. Apart from other lamina propria T lymphocytes in Crohn’s disease. Gut: first published as 10.1136/gut.52.10.1394 on 11 September 2003. Downloaded from ethical aspects, the impact for trans- Gut 2002;50:206–11. plant medicine has to be discussed. How 10 Tiede I, Fritz G, Strand S, et al. should the knowledge be handled about REFERENCES CD28-dependent Rac1 activation is the molecular target of azathioprine in primary genes in organ donors and recipients 1 Duchmann R, Zeitz M. Crohn’s disease. In: human CD4+ T lymphocytes. J Clin Invest that are implicated in the pathogenesis Ogra P, Strober W, eds. Handbook of mucosal 2003;111:1133–45. of disease in a non-monogenetic fashion immunology. San Diego: Academic Press, 11 Sonwalkar SA, James RM, Ahmad T, et al. 1999:1005. Fulminant Crohn’s colitis after allogeneic with varying penetrance? 2 Shanahan F. Crohn’s disease. Lancet stem cell transplantation. Gut With regard to the present case the 2002;359:62–9. 2003;52:1518–21. answer is easy: for the time being our 3 Atreya R, Mudter J, Finotto S, et al. Blockade of 12 Curran ME, Lau KF, Hampe J, et al. Genetic understanding of the role of genetics in interleukin 6 trans signaling suppresses T-cell analysis of inflammatory bowel disease in a large resistance against apoptosis in chronic intestinal European cohort supports linkage to IBD is to preliminary to justify the inflammation: evidence in Crohn disease and chromosomes 12 and 16. Gastroenterology exclusion of a patient with a positive experimental colitis in vivo. Nat Med 1998;115:1066–71. family history for IBD or with proven 2000;6:583–8. 13 Ogura Y, Bonen DK, Inohara N, et al. A 4 Powrie F, Leach MW, Mauze S, et al. Inhibition of genetic susceptibility factors from stem frameshift mutation in NOD2 associated with Th1 responses prevents inflammatory bowel susceptibility to Crohn’s disease. Nature cell donation. In more general terms, disease in scid mice reconstituted with CD45RBhi 2001;411:603–6. however, there will be increasing need CD4+ T cells. Immunity 1994;2:553–62. 14 Hugot JP, Chamaillard M, Zouali H, et al. for debate of this issue in the future. 5 Holtmann MH, Douni E, Schutz M, et al. Tumor Association of NOD2 leucine-rich repeat variants necrosis factor-receptor 2 is upregulated on with susceptibility to Crohn’s disease. Nature Gut 2003;52:1394–1396 lamina propria mononuclear cells in Crohn’s 2001;411:599–603. disease and promotes experimental colitis in vivo. 15 Hisamatsu T, Suzuki M, Reinecker HC, et al...... Eur J Immunol 2002;32:3142–51. CARD15/NOD2 functions as an antibacterial 6 Neurath MF, Fuss I, Kelsall BL, et al. Antibodies to factor in human intestinal epithelial cells. Authors’ affiliations interleukin 12 abrogate established experimental Gastroenterology 2003;124:993–1000. M H Holtmann, M F Neurath, 1st Department colitis in mice. J Exp Med 1995;182:1281–90. 16 Abreu MT, Taylor KD, Lin YC, et al. Mutations in of Medicine, Johannes Gutenberg-University, 7 Lopez-Cubero SA, Sullivan KM, McDonald GB. NOD2 are associated with fibrostenosing disease Mainz, Germany Course of Crohn’s disease after allogenic bone in patients with Crohn’s disease. marrow transplantation. Gastroenterology Gastroenterology 2002;123:679–88. 1998;114:433–40. 17 Scho¨lmerich J. New developments in aetiolo- Correspondence to: Dr M F Neurath, 8 James SP. Remission of Crohn’s disease after gical mechanisms of inflammatory bowel Department of Medicine, Johannes-Gutenberg- human immunodeficiency virus infection. disease. Eur J Gastroenterol Hepatol University, Langenbeckstrasse 1, 55 131 Gastroenterology 1988;95:1667–9. 2003;15:585–6. http://gut.bmj.com/ on September 29, 2021 by guest. Protected copyright.