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A. Introduction [4]navigator

  1. Homocysteine is an amino acid derived from methionine
  2. HC has multiple biological effects, particularly on endothelium
  3. HC Metabolism [1]
    1. Homocysteine metabolism is fairly well understood
    2. Part of the methionine / tetrahydrofolate pathway
    3. Serum HC is derived mainly from dietary methionine
    4. Homocysteine is also a precursor to methionine (MET) and cystathionine
    5. HC conversion to MET catalyzed by methionine synthase (requires vitamin B12)
    6. HC conversion to cystathionine catalyzed by cystathione ß-synthetase + vitamin B6
    7. Elevated plasma HC usually due to heterozygous variants in MTHFR or CBS genes
  4. Levels of HC
    [Figure] "Plasma HC and Mortality"
    1. Nonfasting plasma HC levels are assayed
    2. Normal HC levels are 5-15µmol/L
    3. Moderate elevations are 16-30µmol/L
    4. Intermediate 31-100µmol/L
    5. Severe hyperhomocysteinemia >100µmol/L
  5. Elevated HC Levels [5,6,7]
    1. Increases in HC are strongly associated with extent and level of atherosclerosis
    2. Elevated plasma HC levels increases vascular disease risk >2 fold
    3. Plasma HC levels correlate well with cardiovascular disease and mortality [21]
    4. Increased risk 1.5X (men) to 4X (women) for congestive heart failure (CHF) [31]
    5. Increased risk for venous thromboembolic disease [14]
    6. Increased risk for diabetic retinopathy and nephropathy [10]
    7. Increased risk for stroke (1.2-2.0 fold) in elderly persons [22,28]
    8. Increased risk (~1.5X) for spontaneous abortion [27]
    9. Increased risk for osteoporotic fractures 1.4-4.0 fold [34,35]
    10. Slight (~1.1X) increased risk for ischemic heart disease in general population [28]
    11. Moderately (~1.5X) increased risk for ischemic heart disease in diabetic patients [32]
    12. Elevated HC levels are very uncommon in children (may be related to folate levels)
    13. Large randomized studies failed to show a reduction in vascular events in patients with elevated HC levels treated with folate+Vitamins B6 and B12 [7,8,9,13]
  6. Screening for Elevated HC
    1. Screening plasma HC levels may indentify high risk patients
    2. Methionine loading with pre-/post-methionine HC can identify additional at risk persons
    3. Reduced serum folate levels inversely correlate with cardiovascular risk

B. Classification of Hyperhomocystinemia navigator

  1. Hereditary Homozygous Homocystinuria
    1. Inborn error of metabolism
    2. Usually caused by homozygous cysteine ß-synthetase (CBS) mutations
    3. Homozygous methionine synthetase mutations can cause elevated HC levels
  2. Heterozygous Homocystinemia
    1. Heterozygous carriers of CBS or methionine synthetase mutations
    2. Methylenetetrahydrofolate reductase (MTHFR) mutations also lead to high HC levels
    3. MTHFR 677C±>T polymorphism associated with 1.16X increased risk of ischemic heart disease in patients with reduced folate levels [29]

C. Causes of Elevated HC [3]navigator

  1. HC Metabolic Enzyme Deficiencies (genetic causes; see above)
  2. Vitamin Deficiencies
    1. Folic acid - most common
    2. Vitamin B6 (pyridoxine) - least common
    3. Vitamin B12 (cyanocobalamin)
  3. Smoking
  4. Renal Dysfunction - increased catabolism
  5. Other Diseases
    1. Pernicious anemia (vitamin B12 deficiency)
    2. Atrophic gastritis
    3. Malabsorption syndrome
    4. Hypothyroidism
    5. Psoriasis
    6. Malignancies
    7. Solid organ transplantation
  6. Increased Cell Turnover
    1. Psoriasis (severe)
    2. Systemic Lupus Erythematosus
    3. Malignancy
  7. Hypothyroidism - elevated HC correct with L-thyroxine therapy []
  8. Drugs
    1. Anti-inflammatory: methotrexate, sulfasalazine, cyclosporin A
    2. Nicotinic acid, niacin
    3. Bile acid sequestrants: cholestyramine, colestipol
    4. Anti-seizure: phenytoin, carbamazepine
    5. Thiazide diuretics
    6. Estrogen-containng oral contraceptives
    7. Metformin
    8. Theophylline
  9. Reduced physical activity and increasing age also associated with elevated HC
  10. Male Sex
  11. Menopause
  12. Aging associated with increase in HC levels [30]

D. Hereditary Homocystinuria [14]navigator

  1. Autosomal recessive disease
  2. Screening [15]
    1. Newborn screening is carried out in all patients
    2. Assess all newborns for concentration of methionine (Met) in blood
    3. Normal serum Met value for screening has been changed to 1mg/dL (was 2mg/dL)
    4. Incidence is 1:160,000 (with cutoff methionine value 1mg/dL)
  3. Mechanism
    1. Absence of or severe decrease in cystathionine ß-synthase (CBS)
    2. Patients cannot convert homocysteine (HC) to cysteine
    3. High serum levels of homocysteine lead to disease pathology
    4. Pyridoxine (vitamin B6) is cofactor for cystathionine ß-synthase
    5. Vitamin B12 (cobalamin) and folic acid are cofactors for one recycling pathway
    6. betaine, a choline derivative, is cofactor for the other homocysteine recycling pathway
  4. Signs and Symptoms of Untreated Homocystinuria
    1. Due to elevated plasma levels of HC
    2. Marfenoid appearance with stiff enlarged joints
    3. Thrombotic events
    4. Premature Atherosclerosis
    5. Osteoporosis
    6. Lens dislocation
    7. Psychosis
    8. ~20% of patients will have a thromboembolic event by age 20
  5. Management
    1. High intake of pyridoxine, folic acid and vitamin B12 intake - ~50% patients respond
    2. Add betaine (Cystadane®) 3gm (or higher) po bid [16]
    3. betaine substantially decreases plasma homocysteine levels and is well tolerated [16]
    4. A low methionine or decreased protein diet may also be beneficial

E. Pathophysiology of Elevated HC Levels [17] navigator

  1. Direct endothelial cell toxin and inhibition of nitric oxide production
  2. Causes increased smooth muscle proliferation
  3. Impairs endogenous tissue plasminogen activator (TPA) activity
  4. Platelets: activation, increased thromboxane A2, decreased prostacyclin
  5. Activates clotting Factors V, X, and XII
  6. Inhibition of Antithrombin (AT III) and Protein C
  7. Enhanced lipoprotein (a) binding to fibrin
  8. Increased HC associated with poor outcomes in elderly patients [30]
  9. Nitric oxide (including folate induced) may partially reverse or prevent effects of HC [24]
  10. Pretreatment with vitamins C (1000mg) and E (800IU) blocked effects of HC [17]

F. Treatment navigator

  1. Increasing folate and pyridoxine (Vit B6) intake can reduce HC levels and vascular events [18]
  2. Folic acid supplements reverse the inhibition of nitric oxide production by HC [24]
  3. Fortification of grains with folic acid leads to reductions in HC levels [20]
  4. Supplemental folate + Vit B6 improves exercise electrocardiography in patients at high risk for coronary artery disase [23]
  5. Folate with Vit B6 + B12 Reduce HC Levels [7]
  6. Effects of Vitamin Supplements which reduce HC Levels on Clinical Events [7]
    1. No reduction in clinical events in patients with vascular disease [8]
    2. No reduction in clinical events or mortality in women at high risk of CV disease [13]
    3. No reduction in clinical events when given to patients after acute myocardial infarction [9]
    4. Reducing moderately elevated HC with Vit B6 + B12 + folate after initial nondisabling stroke did not reduce recurrent stroke, MI, or death after 2 years [33]
    5. No improvement in cognitive performance in >65 year olds treated for 2 years [36]
    6. May slow atherosclerosis progression [19]
    7. Reduces major adverse events ~30% after percutaneous coronary interventions (PCI) [26]
    8. Contradictory findings on restenosis following angioplasty [12,25]
    9. Overall, no benefit of reduced HC on reducing vascular events in large trials [7,8,9,13]
  7. Randomized, prospective trials of HC reduction have shown no reduction in thromboembolic events or mortality [7,8,9]

References navigator

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  2. Bots ML, Launer LJ, Lindemans J, et al. 1999. Arch Intern Med. 159(1):38 abstract
  3. Mangoni AA and Jackson SHD. 2002. Am J Med. 112(7):556 abstract
  4. Eikelboom JW, Lonn E, Genest J Jr, et al. 1999. Ann Intern Med. 131(5):363 abstract
  5. Ridker PM, Manson JE, Buring JE, et al. 1999. JAMA. 281(19):1817 abstract
  6. Kark JD, Selhub J, Adler B, et al. 1999. Ann Intern Med. 131(5):321 abstract
  7. Loscalzo J. 2006. NEJM. 354(15):1629 abstract
  8. HOPE-2 Investigators. 2006. NEJM. 354(15):1567 abstract
  9. Bonaa KH, Njolstad I, Ueland PM, et al. 2006. NEJM. 354(15):1578 abstract
  10. Neugebauer S, Baba T, Watanabe T. 1998. Lancet. 352(9126):454 abstract
  11. Bostom AG, Rosenberg IH, Silbershatz H, et al. 1999. Ann Intern Med. 131(5):352 abstract
  12. Lange H, Suryapranata H, De Luca G, et al. 2004. NEJM. 350(26):2673 abstract
  13. Albert CM, Cook NR, Gaziano JM, et al. 2008. JAMA. 299(17):2027 abstract
  14. Ray JG. 1998. Arch Intern Med. 158(19):2101 abstract
  15. Peterschmitt MJ, Simmons JR, Levy HL. 1999. NEJM. 341(21):1572 abstract
  16. betaine. 1997. Med Let. 39(993):12 abstract
  17. Nappo F, De Rosa N, Marfella R, et al. 1999. JAMA. 281(22):2113 abstract
  18. Wald NJ, Watt HC, Law MR, et al. 1998. Arch Intern Med. 158(8):862 abstract
  19. Peterson JC and Spence JD. 1998. Lancet. 351(9098):263 abstract
  20. Levine M, Rumsey SC, Daruwala R, et al. 1999. JAMA. 281(15):1415 abstract
  21. Chambers JC, Obeid OA, Refsum H, et al. 2000. Lancet. 355(9203):523 abstract
  22. Bostom AG, Rosenberg IH, Silbershatz H, et al. 1999. Ann Intern Med. 131(5):352 abstract
  23. Vermeulen EGJ, Stehouwer CDA, Twisk JWR, et al. 2000. Lancet. 355(9203):517
  24. Holven KB, Holm T, Aukrust P, et al. 2001. Am J Med. 110(7):536 abstract
  25. Schnyder G, Roffi M, Pin R, et al. 2001. NEJM. 345(22):1593 abstract
  26. Schnyder C, Roffi M, Flammer Y, et al. 2002. JAMA. 288(8):973 abstract
  27. George L, Mills JL, Johansson AL, et al. 2002. JAMA. 288(15):1867 abstract
  28. Homocysteine Studies Collaboration. 2002. JAMA. 288(16):2015 abstract
  29. Klerk M, Verhoef P, Clarke R, et al. 2002. JAMA. 288(16):2023 abstract
  30. Kado DM, Bucur A, Selhub J, et al. 2002. Am J Med. 113(7):537 abstract
  31. Vasan RS, Beiser A, D'Agostino RB, et al. 2003. JAMA. 289(10):1251 abstract
  32. Soinio M, Marniemi J, Laakso M, et al. 2004. Ann Intern Med. 10(2):95
  33. Toole JF, Malinow MR, Chambless LE, et al. 2004. JAMA. 291(5):565 abstract
  34. Van Meurs JBJ, Dhonukshe-Rutten RAM, Pluijm SMF, et al. 2004. NEJM. 350(20):2033
  35. McLean RR, Jacques PF, Selhub J, et al. 2004. NEJM. 350(20):2042 abstract
  36. McMahon JA, Green TJ, Skeaff M, et al. 2006. NEJM. 354(26):2764 abstract