Hyperhomocysteinemia

From Anvita Health Wiki

Contents 1 Etiology 2 Epidemiology 3 Pathology 4 Laboratory 5 Management 6 More General Terms 7 Additional Terms 8 Internet Database 9 References

Etiology

• enzyme deficiency

• methylene tetrahydrofolate reductase (most common)
• cystathionine beta-synthase ( heterozygous state*)
• methionine synthase

• vitamin deficiency#

• vitamin B12 ( methylcobalamin)
• folic acid ( N5-methyltetrahydrofolate)
• vitamin B6 ( pyridoxal phosphate)

• chronic disease

• chronic renal failure
• systemic lupus erythematosus
• malignant neoplasm
• psoriasis
• hypothyroidism

• acute phase response to systemic illness

• initial reduction of 25%
• convalescent increase to 120% of baseline

• pharmacologic agents

• methotrexate
• nitrous oxide
• antiseizure agents

• phenytoin ( Dilantin)
• carbamazepine ( Tegretol)

• 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

• plasma
• serum

• 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 - Screening for hyperhomocysteinemia:*
• atherosclerosis without conventional risk factors
• premature atherosclerosis (before age 60)
• high risk for premature atherosclerosis

• 1st degree relative with premature atherosclerosis
• tobaccoism
• hypertension

• chronic renal failure
• unexplained deep vein thrombosis (DVT)
• systemic lupus erythematosus
• severe psoriasis
• recipients of solid organ transplant
• pharmacologic agents elevating plasma homocysteine levels

• * screening should be deferred until 8 weeks after recovery from serious systemic illness

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 plamsa 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]

More General Terms

• amino acid inborn error of metabolism
• hypercoagulability

Additional Terms

• homocysteine
• homocysteine in serum/plasma
• homocystinuria
• HOPE-2 trial

Internet Database

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: &dopt=Abstract
2. Medical Knowledge Self Assessment Program (MKSAP) 11, American College of Physicians, Philadelphia 1998
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: [1]
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: [2]
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: [3]
   - Klerk M et al MTHFR 677C-->T polymorphism and risk of coronary heart disease: a meta-analysis. JAMA 288:2023, 2002 PMID: [4]
   - Wilson PW Homocysteine and coronary heart disease: how great is the hazard? JAMA 288:2042, 2002 PMID: [5]
7. 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: [6]
   - 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: [7]
   - Raisz LG Homocysteine and osteoporotic fractures--culprit or bystander? N Engl J Med. 2004 May 13;350(20):2089-90. No abstract available. PMID: [8]
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: [9]
9. Prescriber's Letter 12(9): 2005 High-dose B vitamins and Heart disease Detail-Document#: [10] (subscription needed) [11]
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: [12]
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: [13]
13. Ray JG et al, Homocysteine-lowering therapy and risk for venous thromboembolism: A randomized trial. Ann Intern Med 2007, 246:761 PMID: [14]
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: [15]
    - 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: [16]
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: [17]
16. House AA et al Effect of B-Vitamin Therapy on Progression of Diabetic Nephropathy JAMA. 2010;303(16):1603-1609. <PubMed> PMID: [18] <Internet> [19]

hyperhomocysteinemia