hyperhomocysteinemia
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Etiology
- enzyme deficiency
- methylene tetrahydrofolate reductase (most common)
- cystathionine beta-synthase (heterozygous state*)
- methionine synthase
- vitamin deficiency#
- chronic disease
- acute phase response to systemic illness
- initial reduction of 25%
- convalescent increase to 120% of baseline
- pharmacologic agents
- methotrexate
- nitrous oxide
- antiseizure agents
- nicotinic acid
- colestipol & cholestyramine
- thiazide diuretics
- tobacco use
* homozygous state results in homocystinuria
# cofactor in parenthesis
Epidemiology
- more common with advanced age
- more frequent in men than women
- solid organ transplant recipients
- 30% of patients < 50 years of age with myocardial infarction, stroke or peripheral vascular disease
Pathology
- endothelial cell injury
- impaired endothelium-dependent vasodilation
- impaired endogenous tissue-type plasminogen activator activity
- increased smooth muscle proliferation
- increased platelet activation
- increased synthesis of thromboxane A2
- decreased synthesis of prostacyclin
- abnormalities of the coagulation cascade
- activation of coagulation factors V, X, XII
- inhibition of antithrombin III
- inhibition of protein C
- enhanced binding of lipoprotein<a> to fibrin
- homocysteine levels correlate to fibrinogen levels (an independent risk factor for atherosclerosis)
- increased risk of arterial & venous thrombosis
- premature atherosclerosis (modest risk factor[6])
- homocysteine interferes with normal cross-linking of collagen[7][10]
- 2-4 fold increase risk of hip fracture or osteoporotic fracture
- probably more important in homocystinuria
- may increase risk of dementia, including Alzheimer's disease[5]
Laboratory
- homocysteine levels
- methionine loading test
- baseline homocysteine level
- oral methionine 100 mg/kg
- plasma homocysteine levels 6-8 hours later
- vitamin B12 levels
- vitamin B6 level
- DNA testing for methylene tetrahydrofolate reductase mutation is available
- serum methionine levels are normal or decreased
* see screening for hyperhomocysteinemia
Management
- 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)
- goals
- primary prevention: plasma homocysteine < 14 umol/L
- patients with atherosclerosis:
- plasma homocysteine < 11 umol/L
- correct vitamin B12 deficiency
- multivitamin with 400 ug of folate plus 1 mg folate
- increase folate to 5 mg QD if goal not achieved
- add 400 ug vitamin B12 QD if goal not achieved
- measure vitamin B6 if goal not achieved
- add 50 mg vitamin B6 QD indicated
- consider addition of betaine
- Folgard Rx 2.2 may be useful
- a 2 umol/L decrease in plasma homocysteine may be expected with folate 1 mg, B12 400 ug, pyridoxine 10 mg[4]
- 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]
- supplementation with folate + pyridoxine did not prevent recurrent strokes or heart attacks, despite 28% reduction in serum homocysteine[9]
- combination of folate, vitamin B6, vitamin B12 lowers serum homocysteine, but does not improve outcomes (see HOPE 2 trial)
- supplementation with folate, vit B12 & vit B6 lowers plasma homocysteine but does NOT
- improve cognitive function[11]
- lower risk of DVT or pulmonary embolism[13]
- improve outcomes of patients with chronic renal failure
- risk of myocardial infarction, stroke, amputation or death[14]
- decrease cardiovascular events or mortality[15]
- improve progression of renal insufficiency in patients with diabetic nephropathy[16]
- 0.8 mg of folate/day slows cognitive decline in elderly with hyperhomocysteinemia[12]
- folate lowers serum homocysteine but does not reduce risk of cardiovascular events in patients with kidney disease[15]
More general terms
Additional terms
- homocysteine
- homocysteine in serum/plasma
- homocystinuria
- HOPE-2 trial
- screening for hyperhomocysteinemia
References
- ↑ Stein JH and McBride PE Hyperhomocysteinemia and atherosclerotic vascular disease: pathophysiology, screening, and treatment. Arch Int Med 158:1301 1998 PMID: https://www.ncbi.nlm.nih.gov/pubmed/9645823
- ↑ 2.0 2.1 Medical Knowledge Self Assessment Program (MKSAP) 11, 17. American College of Physicians, Philadelphia 1998, 2015
- ↑ Harrison's Principles of Internal Medicine, 14th ed. Fauci et al (eds), McGraw-Hill Inc. NY, 1998, pg 2199
- ↑ 4.0 4.1 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: https://www.ncbi.nlm.nih.gov/pubmed/11757504
- ↑ 5.0 5.1 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: https://www.ncbi.nlm.nih.gov/pubmed/11844848
- ↑ 6.0 6.1 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: https://www.ncbi.nlm.nih.gov/pubmed/12387654
Klerk M et al MTHFR 677C-->T polymorphism and risk of coronary heart disease: a meta-analysis. JAMA 288:2023, 2002 PMID: https://www.ncbi.nlm.nih.gov/pubmed/12387655
Wilson PW Homocysteine and coronary heart disease: how great is the hazard? JAMA 288:2042, 2002 PMID: https://www.ncbi.nlm.nih.gov/pubmed/12387658 - ↑ 7.0 7.1 Journal Watch 24(12):94, 2004 a) 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: https://www.ncbi.nlm.nih.gov/pubmed/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: https://www.ncbi.nlm.nih.gov/pubmed/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: https://www.ncbi.nlm.nih.gov/pubmed/15141048 - ↑ 8.0 8.1 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: https://www.ncbi.nlm.nih.gov/pubmed/15215483
- ↑ 9.0 9.1 Prescriber's Letter 12(9): 2005 High-dose B vitamins and Heart disease Detail-Document#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=211108&pb=PRL (subscription needed) http://www.prescribersletter.com
- ↑ 10.0 10.1 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
- ↑ 11.0 11.1 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: https://www.ncbi.nlm.nih.gov/pubmed/16807413
- ↑ 12.0 12.1 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: https://www.ncbi.nlm.nih.gov/pubmed/17240287
- ↑ 13.0 13.1 Ray JG et al, Homocysteine-lowering therapy and risk for venous thromboembolism: A randomized trial. Ann Intern Med 2007, 246:761 PMID: https://www.ncbi.nlm.nih.gov/pubmed/17470822
- ↑ 14.0 14.1 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: https://www.ncbi.nlm.nih.gov/pubmed/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: https://www.ncbi.nlm.nih.gov/pubmed/17848657 - ↑ 15.0 15.1 15.2 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: https://www.ncbi.nlm.nih.gov/pubmed/18460663
- ↑ 16.0 16.1 House AA et al Effect of B-Vitamin Therapy on Progression of Diabetic Nephropathy JAMA. 2010;303(16):1603-1609. <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/20424250 <Internet> http://jama.ama-assn.org/cgi/content/full/303/16/1603
- ↑ 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 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/22695899 <Internet> http://www.bmj.com/content/344/bmj.e3533
Haynes R and Clarke R Homocysteine, the kidney, and vascular disease BMJ 2012;344:e3925 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/22695904 <Internet> http://www.bmj.com/content/344/bmj.e3925 - ↑ Ray JG. Hyperhomocysteinemia: no longer a consideration in the management of venous thromboembolism. Curr Opin Pulm Med. 2008 Sep;14(5):369-73 PMID: https://www.ncbi.nlm.nih.gov/pubmed/18664964
- ↑ Gatt A, Makris M. Hyperhomocysteinemia and venous thrombosis. Semin Hematol. 2007 Apr;44(2):70-6. PMID: https://www.ncbi.nlm.nih.gov/pubmed/17433898