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hyperhomocysteinemia

Etiology: 1) enzyme deficiency a) methylene tetrahydrofolate reductase (most common) b) cystathionine beta-synthase (heterozygous state*) c) methionine synthase 2) vitamin deficiency# a) vitamin B12 (methylcobalamin) b) folic acid (N5-methyltetrahydrofolate) c) vitamin B6 (pyridoxal phosphate) 3) chronic disease a) chronic renal failure b) systemic lupus erythematosus c) malignant neoplasm d) psoriasis e) hypothyroidism 4) acute phase response to systemic illness a) initial reduction of 25% b) convalescent increase to 120% of baseline 5) pharmacologic agents a) methotrexate b) nitrous oxide c) antiseizure agents 1] phenytoin (Dilantin) 2] carbamazepine (Tegretol) d) nicotinic acid e) colestipol & cholestyramine f) thiazide diuretics 6) tobacco use * homozygous state results in homocystinuria # cofactor in parenthesis Epidemiology: 1) more common with advanced age 2) more frequent in men than women 3) solid organ transplant recipients 4) 30% of patients < 50 years of age with myocardial infarction, stroke or peripheral vascular disease Pathology: 1) endothelial cell injury a) impaired endothelium-dependent vasodilation b) impaired endogenous tissue-type plasminogen activator activity c) increased smooth muscle proliferation 2) increased platelet activation a) increased synthesis of thromboxane A2 b) decreased synthesis of prostacyclin 3) abnormalities of the coagulation cascade a) activation of coagulation factors V, X, XII b) inhibition of antithrombin III c) inhibition of protein C d) enhanced binding of lipoprotein to fibrin 4) homocysteine levels correlate to fibrinogen levels (an independent risk factor for atherosclerosis) 5) increased risk of arterial & venous thrombosis 6) premature atherosclerosis (modest risk factor [6]) 7) homocysteine interferes with normal cross-linking of collagen [7,10] a) 2-4 fold increase risk of hip fracture or osteoporotic fracture b) probably more important in homocystinuria 8) may increase risk of dementia, including Alzheimer's disease [5] Laboratory: 1) homocysteine levels a) plasma b) serum 2) methionine loading test a) baseline homocysteine level b) oral methionine 100 mg/kg c) plasma homocysteine levels 6-8 hours later 3) vitamin B12 levels 4) vitamin B6 level 5) DNA testing for methylene tetrahydrofolate reductase mutation is available 6) serum methionine levels are normal or decreased * see screening for hyperhomocysteinemia Management: 1) despite status of hyperhomocysteine as risk factors for cardiovascular disease & venous thromboembolism, reduction of plasma homcysteine through supplementation with vitamin B12, folic acid &/or vitamin B6 does not reproducibly improve outcomes [2] (below is a collection of recommendations from conflicting findings) 2) goals a) primary prevention: plasma homocysteine < 14 umol/L b) patients with atherosclerosis: - plasma homocysteine < 11 umol/L 3) correct vitamin B12 deficiency 4) multivitamin with 400 ug of folate plus 1 mg folate 5) increase folate to 5 mg QD if goal not achieved 6) add 400 ug vitamin B12 QD if goal not achieved 7) measure vitamin B6 if goal not achieved -> add 50 mg vitamin B6 QD indicated 8) consider addition of betaine 9) Folgard Rx 2.2 may be useful 10) a 2 umol/L decrease in plasma homocysteine may be expected with folate 1 mg, B12 400 ug, pyridoxine 10 mg [4] 11) a 3 umol/L (12 -> 9) decrease in plasma homocysteine with folate 1.2 mg, B12 60 ug, pyridoxine 48 mg QD did not diminish rate of restenosis in patients with coronary stents [8] 12) supplementation with folate + pyridoxine did not prevent recurrent strokes or heart attacks, despite 28% reduction in serum homocysteine [9] 13) combination of folate, vitamin B6, vitamin B12 lowers serum homocysteine, but does not improve outcomes (see HOPE 2 trial) 14) supplementation with folate, vit B12 & vit B6 lowers plasma homocysteine but does NOT a) improve cognitive function [11] b) lower risk of DVT or pulmonary embolism [13] c) improve outcomes of patients with chronic renal failure - risk of myocardial infarction, stroke, amputation or death [14] d) decrease cardiovascular events or mortality [15] e) improve progression of renal insufficiency in patients with diabetic nephropathy [16] 15) 0.8 mg of folate/day slows cognitive decline in elderly with hyperhomocysteinemia [12] 16) folate lowers serum homocysteine but does not reduce risk of cardiovascular events in patients with kidney disease [15]

Related

homocysteine homocysteine in serum/plasma homocystinuria HOPE-2 trial screening for hyperhomocysteinemia

General

amino acid inborn error of metabolism hypercoagulability

Database Correlations

OMIM 603174

References

  1. Stein JH and McBride PE Hyperhomocysteinemia and atherosclerotic vascular disease: pathophysiology, screening, and treatment. Arch Int Med 158:1301 1998 PMID: 9645823
  2. Medical Knowledge Self Assessment Program (MKSAP) 11, 17. American College of Physicians, Philadelphia 1998, 2015
  3. Harrison's Principles of Internal Medicine, 14th ed. Fauci et al (eds), McGraw-Hill Inc. NY, 1998, pg 2199
  4. Journal Watch 22(1):2, 2002 Brown BG et al Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med 345:1583, 2001 PMID: 11757504
  5. Journal Watch 22(7):56-57, 2002 Seshadri S et al Plasma homocysteine as a risk factor for dementia and Alzheimer's disease. N Engl J Med 346:476, 2002 PMID: 11844848
  6. Journal Watch 22(24):181, 2002 Homocysteine Studies Collaboration Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis. JAMA 288:2015, 2002 PMID: 12387654 - Klerk M et al MTHFR 677C-->T polymorphism and risk of coronary heart disease: a meta-analysis. JAMA 288:2023, 2002 PMID: 12387655 - Wilson PW Homocysteine and coronary heart disease: how great is the hazard? JAMA 288:2042, 2002 PMID: 12387658
  7. Journal Watch 24(12):94, 2004
    1. van Meurs JB et al Homocysteine levels and the risk of osteoporotic fracture. N Engl J Med. 2004 May 13;350(20):2033-41. PMID: 15141041 - McLean RR et al Homocysteine as a predictive factor for hip fracture in older persons. N Engl J Med. 2004 May 13;350(20):2042-9. PMID: 15141042 - Raisz LG Homocysteine and osteoporotic fractures--culprit or bystander? N Engl J Med. 2004 May 13;350(20):2089-90. No abstract available. PMID: 15141048
  8. Lange H, Suryapranata H, De Luca G, Borner C, Dille J, Kallmayer K, Pasalary MN, Scherer E, Dambrink JH. Folate therapy and in-stent restenosis after coronary stenting. N Engl J Med. 2004 Jun 24;350(26):2673-81. PMID: 15215483
  9. Prescriber's Letter 12(9): 2005 High-dose B vitamins and Heart disease Detail-Document#: 211108 (subscription needed) http://www.prescribersletter.com
  10. Sato Y, Iwamoto J, Kanoko T, Satoh K Homocysteine as a predictive factor for hip fractures in elderly women with Parkinson's disease American Journal of Medicine 118:1250, 2005
  11. McMahon JA, Green TJ, Skeaff CM, Knight RG, Mann JI, Williams SM. A controlled trial of homocysteine lowering and cognitive performance. N Engl J Med. 2006 Jun 29;354(26):2764-72. PMID: 16807413
  12. Durga J et al, Effect of 3-year folic acid supplementation on cognitive function in older adults in the FACIT trial: a randomised, double blind, controlled trial. Lancet. 2007 Jan 20;369(9557):208-16. PMID: 17240287
  13. Ray JG et al, Homocysteine-lowering therapy and risk for venous thromboembolism: A randomized trial. Ann Intern Med 2007, 246:761 PMID: 17470822
  14. Jamison RL, Hartigan P, Kaufman JS, Goldfarb DS, Warren SR, Guarino PD, Gaziano JM; Veterans Affairs Site Investigators. Effect of homocysteine lowering on mortality and vascular disease in advanced chronic kidney disease and end-stage renal disease: a randomized controlled trial. JAMA. 2007 Sep 12;298(10):1163-70. PMID: 17848650 - Baigent C, Clarke R. B vitamins for the prevention of vascular disease: insufficient evidence to justify treatment. JAMA. 2007 Sep 12;298(10):1212-4. No abstract available. PMID: 17848657
  15. Albert CM et al. Effect of folic acid and B vitamins on risk of cardiovascular events and total mortality among women at high risk for cardiovascular disease: A randomized trial. JAMA 2008 May 7; 299:2027 PMID: 18460663
  16. House AA et al Effect of B-Vitamin Therapy on Progression of Diabetic Nephropathy JAMA. 2010;303(16):1603-1609. PMID: 20424250 http://jama.ama-assn.org/cgi/content/full/303/16/1603
  17. Jardine MJ et al The effect of folic acid based homocysteine lowering on cardiovascular events in people with kidney disease: systematic review and meta-analysis BMJ 2012;344:e3533 PMID: 22695899 http://www.bmj.com/content/344/bmj.e3533 - Haynes R and Clarke R Homocysteine, the kidney, and vascular disease BMJ 2012;344:e3925 PMID: 22695904 http://www.bmj.com/content/344/bmj.e3925
  18. Ray JG. Hyperhomocysteinemia: no longer a consideration in the management of venous thromboembolism. Curr Opin Pulm Med. 2008 Sep;14(5):369-73 PMID: 18664964
  19. Gatt A, Makris M. Hyperhomocysteinemia and venous thrombosis. Semin Hematol. 2007 Apr;44(2):70-6. PMID: 17433898