Nutrition Volume 16, Number 9, 2000
REFERENCES 1. Lowry SF. Hormone and cytokine regulation of injury metabolism. In: Vincent JL, ed. Yearbook of intensive care and emergency medicine. Berlin: Springer Verlag, 1993:3 2. Kinney JM, Elwyn DH. Protein metabolism and injury. Ann Rev Nutr 1983;3: 433 3. Giesecke K, Klingstedt C, Ljungqvist O, Hagenfeldt L. The modifying influence of anesthesia on postoperative protein catabolism. Br J Anaesth 1994;72:697 4. Schricker T, Carli F, Schreiber M, et al. Propofol/sufentanil anesthesia suppresses the metabolic and endocrine response during, not after lower abdominal surgery. Anesth Analg 2000;90:450 5. Mertes N, Goetters C, Kuhlmann M, Zander JF. Postoperative alpha-2 adrenergic stimulation attenuates protein catabolism. Anesth Analg 1996;82:258 6. Metz SA, Halter JB, Robertson RP. Induction of defective insulin secretion and impaired glucose tolerance by clonidine. Selective stimulation of metabolic alpha adrenergic pathways. Diabetes 1978;27:554 7. Kehlet H. Modification of responses to surgery by neural blockade. In: Cousins MJ, Bridenbaugh PO, eds. Neural Blockade in Clinical Anesthesia and Management of Pain. Philadelphia: Lippincott-Raven Publishers, 1998:129 8. Carli F, Webster J, Pearson M, et al. Protein metabolism after abdominal surgery: effect of 24-H extradural block with local anaesthetic. Br J Anaesth 1991;67:729 9. Carli F, Halliday D. Continuous epidural blockade arrests the postoperative decrease in muscle protein fractional synthetic rate in surgical patients. Anesthesiology 1997;86:1033 10. Schricker T, Wykes L, Carli F. Epidural blockade improves substrate utilization after surgery. Am J Physiol (in press) 11. Ferrando AA, Lane HW, Stuart CA, et al. Prolonged bed rest decreases skeletal muscle and whole body protein synthesis. Am J Physiol 1996;270:E627 12. Kehlet H, Nielsen HJ. Impact of laparoscopic surgery on stress responses, immunofunction, and risk of infectious complications. New Horizons 1998;6:S80 13. Nordenstro¨m J, Askanazi J, Elwyn DH, et al. Nitrogen balance during total parenteral nutrition. Ann Surg 1983;197:27 14. Shaw JHF, Wolfe RR. An integrated analysis of glucose, fat, and protein metabolism in severely traumatized patients. Ann Surg 1989;209:63 15. Schricker T, Lattermann R, Schreiber M, et al. The hyperglycaemic response to surgery: pathophysiology, clinical implications and modification by the anaesthetic technique. Clinical Intensive Care 1998;9:118 16. Klein S, Kinney J, Jeejeeboy K, et al. Nutrition support in clinical practice: review of published data and recommendations for future research directions. JPEN 1997;21:133 17. Heslin MJ, Latkany L, Leung D, et al. A prospective randomized trial of early enteral feeding after resection of upper GI malignancy. Ann Surg 1997;266:567 18. Kudsk KA, Croce MA, Fabian TC, et al. Enteral versus parenteral feedings: effects on septic morbidity after blunt and penetrating abdominal trauma. Ann Surg 1992;215:503 19. Nygren J, Thorell A, Soop M. Perioperative insulin and glucose infusion maintains normal insulin sensitivity after surgery. Am J Physiol 1998;275:E140 20. Sieber FE, Smith DS, Traystman RJ, Wollman H. Glucose: a reevaluation of its intraoperative use. Anesthesiology 1987;67:72 21. Stehle P, Zander J, Mertes N, et al. Effect of parenteral glutamine peptide supplements on muscle glutamine loss and nitrogen balance after major surgery. Lancet 1989;1:231 22. Ziegler TR, Young IS, Benfell K, et al. Clinical and metabolic efficacy of glutamine-supplemented parenteral nutrition following bone marrow transplantation: a randomized, doubleblind controlled trial. Ann Intern Med 1992;116:821 23. Griffiths RD, Jones C, Palmer TEA. Six month outcome of critically ill patients given glutamine supplemented parenteral nutrition. Nutrition 1997;13:295 24. Woolfson AMJ, Heatley RV, Allison SP. Insulin to inhibit protein catabolism after surgery. N Engl J Med 1979;300:14 25. Sakurai M, Aarsland A, Herndon DN, et al. Stimulation of muscle protein synthesis by long-term insulin infusion in severely burned patients. Ann Surg 1995;222:283 26. Jiang ZM, He GZ, Zhang SY, et al. Low-dose growth hormone and hypocaloric nutrition attenuate the protein-catabolic response following major operation. Ann Surg 1989;210:513 27. Knox JB, Wilmore DW, Demling RH, et al. Use of growth hormone for postoperative respiratory failure. Am J Surg 1996;171:576 28. Carli F, Webster JD, Halliday D. Growth hormone modulates amino acid oxidation in the surgical patient: leucine kinetics during the fasted and fed state using moderate nitrogenous and caloric diet and recombinant human growth hormone. Metabolism 1997;46:23 29. Takala Y, Ruokonen E, Webster N, et al. Increased mortality associated with growth hormone treatment in critically ill patients. N Engl J Med 1999;341:785
Homocysteine: More Questions Than Answers In recent years, homocysteine has emerged to rival cholesterol as an independent marker for vascular disease. It is now commonly accepted that total serum homocysteine is a risk factor for premature atherosclerosis and atherothrombosis of the coronary, cerebral, and peripheral vascular beds.1 Serum homocysteine has also been shown to be an independent predictor of mortality in patients with known coronary artery disease.2 Data from the European Concerted Action Project suggest that an elevated serum homocysteine level interacts with conventional risk factors to further increase vascular disease risk.3 The debate continues as to whether elevated serum homocysteine is a causative factor in the pathogenesis of vascular disease or merely a marker for such an ongoing process. However, because an elevated serum homocysteine concentration is a potentially modifiable risk factor, there has been a significant amount of interest in identifying the causes and implications of increased serum homocysteine concentrations. Regardless of its effects, the only currently recognized end-organ damage associated with hyperhomocysteinemia is within the vascular system. Just as with plasma cholesterol, serum homocysteine concentrations can be determined by both genetic and nutritional factors. Genetic causes of elevated serum homocysteine include defects in the enzymatic machinery responsible for the regulation of homocysteine metabolism while nutritional causes include deficiencies of folate, vitamin B6 or vitamin B12.4 Given the central roles these vitamin cofactors play in homocysteine metabolism (folate and vitamin B12 are necessary for recycling via remethylation, while vitamin B6 is required for degradation by the transsulfuration pathway), an inverse relationship between serum vitamin concentrations and tHcy is not surprising.1 An association of elevated homocysteine and a deficiency of another vitamin or mineral cofactor has not been previously described. There are now numerous studies demonstrating that serum homocysteine concentrations can be lowered by vitamin supplementation in patients with documented vitamin deficiencies.4,5 Although various combinations of folic acid, vitamin B6, and vitamin B12 have demonstrated the ability to lower serum homocysteine concentrations, folate is the most likely effective agent. Folic acid is the only vitamin supplement shown to consistently reduce serum homocysteine when given alone or in the absence of vitamin deficiency. Because folate supplements are relatively safe and inexpensive, policies promoting widespread supplementation or fortification have been proposed. Advocates commonly cite the gradual reduction since 1960 in US mortality from cardiovascular causes, which correlates with supplementation of the food supply with vitamin B6.6 However, critics suggest that routine folate supplementation may mask the hematologic manifestations of pernicious anemia, allowing its irreversible neurologic manifestations to progress unrecognized until a later stage in the disease process.7 Turning our interest to the study by Thomson et al.8 in the June issue of Nutrition, we find the results of their moderate-sized case control study which examines the correlates of total plasma homocysteine in women with cervical intraepithelial neoplasia. In this patient-population plasma folate, RBC folate and plasma vitamin B12 concentrations were inversely correlated with plasma homocysteine, confirming that folate and vitamin B12 are significant determinants of serum homocysteine. Daily folic acid supplementation (10 mg/d) in these patients for 6 mo significantly lowered mean tHcy in all patient groups when compared to baseline or
Correspondence to: Lee E. Morrow, MD, Washington University, BarnesJewish Hospitals, 7736 Cornell Avenue, St. Louis, MO 63130, USA.
Nutrition Volume 16, Number 9, 2000 placebo controls. These results are again consistent with previous publications. An intriguing new finding we’ve discovered is that plasma copper concentration is positively correlated with tHcy. The statistical significance of elevated copper does not seem to be caused by confounding from another variable. Interpretation of this finding is at best speculative, as there is a paucity of data linking copper and homocysteine concentrations. Interestingly, Bethin et al. have previously reported that copper-binding protein from mouse liver is the same protein as human placental S-adenosylhomocysteine hydrolase.9 This enzyme is known to cleave the adenosine entity from S-adenosyl homocysteine– yielding adenosine and homocysteine as metabolic bi-products. On this basis, a link between copper and homocysteine is theoretically plausible. However, given the lack of data on the topic, it remains to be seen whether an elevated serum copper level is an etiologic factor or simply an incidental surrogate marker of increased serum homocysteine. Another novel finding in the Thompson et al. study is that the severity of cervical dysplasia is positively correlated with serum homocysteine concentration. This appears to be the first description of elevated serum homocysteine in association with a pathologic process beyond the vascular system. As such, the explanation of such a finding is purely conjecture. Although not specifically addressed by the authors, it should again be noted that these patients also had elevated levels of copper in their system. As such, it is unclear how much relative contribution, if any, homocysteine and copper have in the pathogenesis of cervical dysplasia. These puzzling findings should serve to remind us that our understanding of homocysteine is in its infancy and will require an immense research investment in the future. To date, no prospective, randomized clinical trials have been performed that have demonstrated reduction of serum homocysteine by vitamin supplementation will reduce vascular events. As such, it is impossible to clearly translate our current understanding of homocysteine and its metabolism into meaningful, clinical recommendations. However, at least 10 large clinical trials are
currently underway to provide the definitive answers we require. While the results of such trials will have important implications on clinical practice, these studies will require many years to generate convincing results. Until these pivotal studies are completed, the role of routine homocysteine screening and prescription of vitamin supplementation remain unjustified. The best clinical recommendation in the interim continues to be a prudent low-cholesterol diet. Such a diet, in addition to its benefits on serum lipids, will provide an adequate amount of folic acid, vitamin B6, and vitamin B12, minimizing the need for pharmacologic supplementation.
Lee E. Morrow, MD Barnes-Jewish Hospitals Washington University St. Louis, Missouri, USA REFERENCES 1. Welch GN, Loscalzo J. Homocysteine and atherothrombosis. NEJM 1998;338: 1042 2. Nygard O, Nordrehaug JE, Refsum H, et al. Plasma homocysteine levels and mortality in patients with coronary artery disease. NEJM 1997;337:230 3. Graham IM, Daly LE, Refsum IM, et al. Plasma homocysteine as a risk factor for vascular disease. The European Concerted Action Project. JAMA 1997;277:1775 4. Selhub J, Jacques PF, Wilson PW, et al. Vitamin status and intake as primary determinants of homocysteinemia in an elderly population. JAMA 1993;270:2693 5. Brattstrom L. Vitamins as homocysteine-lowering agents. J Nutr 1996;126:1276S 6. McCully KS. Homocysteine and vascular disease. Nat Med 1996;2:386 7. Savage DG, Lindenbaum J. Folate-cobalamin interactions. In: Bailey LB, ed. Folate in health and disease. New York: Marcel Dekker Inc. 1995;237 8. Thomson SW, Heimburger DC, Cornwell PE, et al. Correlates of total plasma homocysteine: folic acid, copper, and cervical dysplasia. Nutrition 2000;16:411 9. Bethin KE, Petrovic N, Ettinger MJ. Identification of a major hepatic copper binding protein as S-adenosylhomocysteine hydrolase. J Biol Chem 1994;270: 20698