The Effects of Homocysteine Level in the Critically Ill Patient. A Review

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Increased levels of homocysteine (HCYS) represent a risk factor for a series of physiopathological conditions: mental retardation, cardiovascular and neurodegenerative diseases, Parkinson's and Alzheimer's disease, depression, osteoporosis, endothelial dysfunction and inhibition of cell proliferation. This paper aims to present the pathophysiological implications of HCYS and the correlation of hyperhomocysteinemia (H-HCYS) with critical condition in the intensive care unit (ICU). Hypovitaminosis B and folate deficiency is directly involved in the inhibition of HCYS metabolism and the accumulation of HCYS in the plasma and tissues. Critically ill patients are more prone to H-HCYS due to hypermetabolism and accelerated synthesis produced by reactive oxygen species (ROS). In conclusion it can be affirmed that the determination and monitoring of HCYS plasma levels may be of interest in optimizing the therapy for critically ill patients. Moreover, by controlling HCYS levels, and implicitly the essential cofactors that intervene in the specific biochemical pathways, such as vitamin B6, vitamin B12 and folic acid can provide a diversified and personalized treatment for each patient.

1. Miller AL, Kelly GS. Homocysteine Metabolism: Nutritional Modulation and Impact on Health and Disease Homocysteine. Alt Med Rev. 1997;2(4):234-254.

2. Eldeen ON, Abd Eldayem SM, Shatla RH, Omara N, Elgammal SS. Homocysteine, folic acid and vitamin B12 levels in serum of epileptic children. Egypt J Med Hum Genet. 2012;13(3):275-280.

3. Schaffer A, Verdoia M, Cassetti E, Marino P, Suryapranata H, De Luca G. Relationship between homocysteine and coronary artery disease. Results from a large prospective cohort study. Thromb Res. 2014.134:288-93.

4. Christie L, Riedel G, Algaidi S, Whalley LJ, Platt B. Enhanced hippocampal long-term potentiation in rats after chronic exposure to homocysteine. Neurosci Lett. 2005;373:119-124.

5. Kloppenborg RP, Nederkoorn PJ, van der Graaf Y, Geerlings MI. Homocysteine and cerebral small vessel disease in patients with symptomatic atherosclerotic disease. The SMART-MR study. Atherosclerosis. 2011;216(2):461-466.

6. de Jager C. Critical levels of brain atrophy associated with homocysteine and cognitive decline. Neurobiol Aging. 2014;35:S35-S39.

7. Jendricko T, Vidović A, Grubisić-Ilić M, Romić Z, Kovacić Z, Kozarić-Kovacić D. Homocysteine and serum lipids concentration in male war veterans with posttraumatic stress disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2009;33(1):134-140.

8. Douaud G, Refsum H, Jager CA De, Jacoby R, Nichols TE. Preventing Alzheimer’s disease-related gray matter atrophy by B-vitamin treatment. Gwenaëlle Douaud. 2013;110:9523-9528.

9. Song IU, Kim JS, Park IS, et al. Clinical significance of homocysteine (hcy) on dementia in Parkinson’s disease (PD). Arch Gerontol Geriatr. 2013;57(3):288-291.

10. Allam A, Ammar H, Radwan A. Serum homocysteine level and eye involvement in Egyptian patients with Behçet’s disease. Egypt Rheumatol. 2014;36(1):29-34.

11. Wijngaarden JP Van, Doets EL, Szczeci N, et al. Vitamin B 12, Folate, Homocysteine, and Bone Health in Adults and Elderly People: A Systematic Review with Meta-Analyses. J Nutr Metab. 2013;2013.

12. Ramakrishnan S, Sulochana KN, Lakshmi S, Selvi R, Angayarkanni N. Biochemistry of homocysteine in health and diseases. Indian J Biochem Biophys. 2006;43:275-283.

13. Ruseva S, Lozanov V, Markova P, Girchev R, Mitev V. In vivo investigation of homocysteine metabolism to polyamines by high-resolution accurate mass spectrometry and stable isotope labeling. Anal Biochem. 2014;457:38-47.

14. Lippi G, Mattiuzzi C, Meschi T, Cervellin G, Borghi L. Homocysteine and migraine. A narrative review. Clin Chim Acta. 2014;433:5-11.

15. Tehlivets O, Malanovic N, Visram M, Pavkov-Keller T, Keller W. S-adenosyl-L-homocysteine hydrolase and methylation disorders: Yeast as a model system. Biochim Biophys Acta - Mol Basis Dis. 2013;1832(1):204-215.

16. Maclean KN, Sikora J, Kožich V, et al. Cystathionine beta-synthase null homocystinuric mice fail to exhibit altered hemostasis or lowering of plasma homocysteine in response to betaine treatment. Mol Genet Metab. 2010;101:163-171.

17. Meng X, Ye W, Wang S, et al. A ratiometric two-photon fluorescent probe for cysteine and homocysteine in living cells. Sensors Actuators, B Chem. 2014;201:520-525.

18. Wei X, Gong C, Gou M, et al. Biodegradable poly(epsilon-caprolactone)-poly(ethylene glycol) copolymers as drug delivery system. Int J Pharm. 2009;381(1):1-18.

19. Choe YM, Sohn BK, Choi HJ, et al. Association of homocysteine with hippocampal volume independent of cerebral amyloid and vascular burden. Neurobiol Aging. 2014;35(7):1519-1525.

20. Lan T-H, Xu Z-W, Wang Z, Wu Y-L, Wu W-K, Tan H-M. Ginsenoside Rb1 prevents homocysteine-induced endothelial dysfunction via PI3K/Akt activation and PKC inhibition. Biochem Pharmacol. 2011;82(2):148-155.

21. Jeong S-K, Kim D-H, Cho YI. Homocysteine and pulsatility index in lacunar infarction. Clin Neurol Neurosurg. 2011;113(6):459-463.

22. Agnati LF, Genedani S, Rasio G, et al. Studies on homocysteine plasma levels in Alzheimer’s patients. Relevance for neurodegeneration. J Neural Transm. 2005;112:163-169.

23. Genedania S, Rasiob G, Cortellic P, et al. Studies on Homocysteine and Dehydroepiandrosterone Sulphate Plasma Levels in Alzheimer’s Disease Patients and in Parkinson’s Disease Patients. Neurotox Res. 2004;6(4):327-332.

24. Jami M-S, Pal R, Hoedt E, Neubert T, Larsen JP, Møller SG. Proteome analysis reveals roles of L-DOPA in response to oxidative stress in neurons. BMC Neurosci. 2014;15:93.

25. Bouaziz N, Ayedi I, Sidhom O, et al. Plasma homocysteine in schizophrenia: Determinants and clinical correlations in Tunisian patients free from antipsychotics. Psychiatry Res. 2010;179:24-29.

26. Nagaraja D, Noone ML, Bharatkumar VP, Christopher R. Homocysteine, folate and vitamin B(12) in puerperal cerebral venous thrombosis. J Neurol Sci. 2008;272(1-2):43-47.

27. Glover AT, Shaw SM, Williams SG, Fildes JE. Can inflammation be an independent predictor of depression? Brain Behav Immun. 2010;24(2):173;174-175.

28. Steptoe A, Hamer M, Chida Y. The effects of acute psychological stress on circulating inflammatory factors in humans: a review and meta-analysis. Brain Behav Immun. 2007;21(7):901-912.

29. Obeid R, Herrmann W. Mechanisms of homocysteine neurotoxicity in neurodegenerative diseases with special reference to dementia. FEBS Lett. 2006;580:2994-3005.

30. Möller M, Du Preez JL, Viljoen FP, Berk M, Emsley R, Harvey BH. Social isolation rearing induces mitochondrial, immunological, neurochemical and behavioural deficits in rats, and is reversed by clozapine or N-acetyl cysteine. Brain Behav Immun. 2013;30:156-167.

31. Enneman a W, Swart KM a, Zillikens MC, et al. The association between plasma homocysteine levels and bone quality and bone mineral density parameters in older persons. Bone. 2014;63:141-146.

32. Ataie A, Ataee R, Mansoury Z, Aghajanpour M, Sciences M. Homocysteine Intracerebroventricular Injection Induces Apoptosis in the Substantia Nigra Cells and Parkinson’s Disease Like Behavior in Rats. Int J Mol Cell Med. 2013;(3):2-7.

33. Bertoia ML, Pai JK, Cooke JP, et al. Plasma homocysteine, dietary B vitamins, betaine, and choline and risk of peripheral artery disease. Atherosclerosis. 2014;235(1):94-101.

34. Schnabel R, Lackner KJ, Rupprecht HJ, et al. Glutathione peroxidase-1 and homocysteine for cardiovascular risk prediction: results from the AtheroGene study. J Am Coll Cardiol. 2005;45(10):1631-1637.

35. Maric T, Woodside B, Luheshi GN. The effects of dietary saturated fat on basal hypothalamic neuroinflammation in rats. Brain Behav Immun. 2014;36:35-45.

36. Giustarini D, Fanti P, Sparatore A, Matteucci E, Rossi R. Anethole dithiolethione lowers the homocysteine and raises the glutathone levels in solid tissues and plasma of rats: A novel non-vitamin homocysteine-lowering agent. Biochem Pharmacol. 2014;89(2):246-254.

37. Amorim De Farias Leal A, Camêlo Palmeira Á, et al. Homocysteine: cardiovascular risk factor in children and adolescents? Rev Assoc Med Bras. 2013;59(6):622-628.

38. Santos MERC, Das CLE Silva F, Gomes KB, et al. Mutations in methylenetetrahydrofolate reductase and in cysthationine beta synthase: Is there a link to homocysteine levels in peripheral arterial disease? Mol Biol Rep. 2011;38:3361-3366.

39. Zoccolella S, Tortorella C, Iaffaldano P, et al. Elevated plasma homocysteine levels in patients with multiple sclerosis are associated with male gender. J Neurol. 2012;259:2105-2110.

40. Liu Y, Tian T, Zhang H, Gao L, Zhou X. The effect of homocysteine-lowering therapy with folic acid on flow-mediated vasodilation in patients with coronary artery disease: A meta-analysis of randomized controlled trials. Atherosclerosis. 2014;235(1):31-35.

41. Stoiser B, Thalhammer F, El-Menyawi I, et al. Homocysteine and laminin are not prognostic markers in patients with septic inflammatory response syndrome. Clin Diagn Lab Immunol. 2000;7(1):119-121.

42. Konrad C, Müller G a., Langer C, et al. Plasma homocysteine, MTHFR C677T, CBS 844ins68bp, and MTHFD1 G1958A polymorphisms in spontaneous cervical artery dissections. J Neurol. 2004;251(10):1242-1248.

43. Kuyumcu ME, Yesil Y, Oztürk ZA, et al. The association between homocysteine (hcy) and serum natural antioxidants in elderly bone mineral densitometry (BMD). Arch Gerontol Geriatr. 2012;55(3):739-743.

44. Poloni S, Leistner-Segal S, Bandeira IC, et al. Body composition in patients with classical homocystinuria: body mass relates to homocysteine and choline metabolism. Gene. 2014;546(2):443-447.

45. Rehackova P, Skalova S, Kutilek S. Serum homocysteine levels in children and adolescents with impaired bone health. Rev Bras Reumatol. 2013;53(6):464-469.

46. Tyagi N, Vacek TP, Fleming JT, Vacek JC, Tyagi SC. Hyperhomocysteinemia decreases bone blood flow. Vasc Health Risk Manag. 2011;7:31-35.

47. Ploder M, Kurz K, Spittler A, Neurauter G, Roth E, Fuchs D. Early increase of plasma homocysteine in sepsis patients with poor outcome. Mol Med. 2010;16:498-504.

48. Omar A, El-Shahat N, Ramadan MM. Cardiac functions in patients with sepsis and septic shock. Egypt Hear J. 2012;64(4):191-196.

49. Bramlett K, Onel E, Viscusi ER, Jones K. A randomized, double-blind, dose-ranging study comparing wound infiltration of DepoFoam bupivacaine, an extended-release liposomal bupivacaine, to bupivacaine HCl for postsurgical analgesia in total knee arthroplasty. Knee. 2012;19(5):530-536.

50. Lee LM, Chang LC, Wrobleski S, Wakefield TW, Yang VC. Low molecular weight protamine as nontoxic heparin/low molecular weight heparin antidote (III): preliminary in vivo evaluation of efficacy and toxicity using a canine model. AAPS PharmSci. 2001;3(2):E19.

51. Wang C, Chen Z, Zhang T, et al. Elevated plasma homocysteine level is associated with ischemic stroke in Chinese hypertensive patients. Eur J Intern Med. 2014;25(6):538-544.

52. Zeckey C, Dannecker S, Hildebrand F, et al. Alcohol and multiple trauma: is there an influence on the outcome? Alcohol. 2011;45(3):245-251.

53. Shuwei D, Shuwen L, Xuefeng S, et al. Potential association of hyperhomocysteinemia with the. Chim Med J. 2014;127(10).

54. Shepherd L, Wild J. Emotion regulation, physiological arousal and PTSD symptoms in trauma-exposed individuals. J Behav Ther Exp Psychiatry. 2014;45(3):360-367.

55. Ontario HQ. Vitamin B12 and cognitive function: an evidence-based analysis. Ont Health Technol Assess Ser. 2013;13(23):1-45.

56. Pascoe MC, Crewther SG, Carey LM, Noonan K, Crewther DP, Linden T. Homocysteine as a potential biochemical marker for depression in elderly stroke survivors. Food Nutr Res. 2012;1:1-5.

57. Fazal N, Shelip A, Alzahrani AJ. Burn-injury affects gut-associated lymphoid tissues derived CD4+ T cells. Results Immunol. 2013;3:85-94.

58. Moorthy D, Peter I, Scott TM, et al. Status of Vitamins B-12 and B-6 but Not of Folate, Homocysteine, and the Methylenetetrahydrofolate Reductase C677T Polymorphism Are Associated with Impaired Cognition and Depression in Adults. J Nutr. 2012;142(8):1554-1560.

59. Nachum-biala Y, Troen AM. B-vitamins for neuroprotection: Narrowing the evidence gap. Biofactors. 2012;38(2):145-150.

60. Koz ST, Etem EO, Baydas G, et al. Effects of resveratrol on blood homocysteine level, on homocysteine induced oxidative stress, apoptosis and cognitive dysfunctions in rats. Brain Res. 2012;1484:29-38.

61. Ohashi R, Yan S, Mu H, et al. Effects of homocysteine and ginsenoside Rb1 on endothelial proliferation and superoxide anion production. J Surg Res. 2006;133(2):89-94.

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