05 November 2004
Homocystinuria : uncommon autosomal recessive disorder involving defective cystathionine B synthase enzyme resulting in elevated levels of homocyst(e)ine in plasma and urine with excessive morbidity & mortality from premature vascular events.
PATHWAYS: (Click here)
McKully in American Journal of Pathology 1969
Infant with rare disorder of cobalamin metabolism whom at postmortem was found to have widespread severe arteriosclerosis similiar to that found in homocystinuric patients.
hyperhomocyst(e)inemia was associated with arteriosclerosis.
Homocystine is oxidised (disulfide) form of homocysteine (sulfhydryl).
Plasma homocyst(e)ine levels is total of
1.80% protein bound homocyst(e)ine
Hyperhomocyst(e)inemia: fasting level >15 micromol/l
(methionine loading test occasionally used; similiar to glucose tolerance test)
FACTORS INFLUENCING HOMOCYST(E)INE LEVELS
HYPERHOMOCYST(E)NEMIA AS A CARDIOVASCULAR RISK FACTOR
Stamper et al. A prospective study of plasma homocyst(e)ine levels and risk of myocardial infarction in US physicians. JAMA Aug1992, 268(7), 877-881.
RR3.4 in highest 5 centile (correlated to >15.8 uM homocyst(e)ine) compared to bottom 90 centile. Result took into account hypertension, diabetes, aspirin, cholesterol & smoking. CI 1.4-6.9. P<0.005.
Most studies predominantly case control studies showing association not causation.
Independent risk factor for coronary artery disease.
As significant a risk factor as hypercholesteremia?
a.baboons with 5 day infusion of homocyst(e)ine had evidence of endothelial desquamation & reduced platelet survival.
b.baboons with 3 months infusion of homocysteine evidence of endothelial desquamation & subintimal fibrosis
c.post mortem findings of homocystinurics: marked fibrous thickening of subintimal region, frayed muscle fibres & increased interstitial collagen in media. NB no lipid deposition
a.reduced platelet survival time
b.increased adhesiveness of platelets
a.reduced antithrombin activity (normalises with pyridoxine & folic acid)
b.homocyst(e)ine activates factor V in dose dependent manner
REDUCTION OF HOMOCYST(E)INE LEVELS
1.Treat underlying cause
c.B6(pyridoxine) (SE sensory neuropathy, ataxia)
e.Methionine restricted diet (essential amino acid!!)
650 microgram folate will reduce homocyst(e)ine levels by 42%
effects of folate plateau off at 1000 microgram/day
200 micrograms/day will reduce homocyst(e)ine by 4 uM
folate will normalise levels in majority of patients
folate+B12+B6+Betaine will reduce levels by 53%
B6 supplementation will improve response to methionine challenge but not alter fasting levels.
minimum requirement for folate is 50 microgram/day
RDA 250 microgram/day
3 servings of fruit & vegetables carries 100 microgram folate
Proposal in US re fortification of food(grains) with folate at 350microgram/100 mg.
danger of ppt B12 def/SACD therefore 1mg B12 to be added
Boushey et al. A quantitative assessment of plasma homocyst(e)ine as a risk factor for vascular disease. JAMA Oct1995 274(13): 1049-52.
Hyperhomocyst(e)inemia is associated with increased risk for coronary artery disease with RR3.4
Folic acid supplementation will reduce plasma homocyst(e)ine levels.
>400 microgram/day of folate will normalise homocyst(e)ine levels in majority of patients.
Mechanism whereby homocyst(e)ine causes vascular disease in humans.
Reduction in homocyst(e)ine levels will reduce risk of vascular disease.
Future trials will be more difficult in US with new folate/B12 fortification laws coming in to place especially in regards to assessing effectiveness of folate supplementation. (Benefits pregnant woman for prevention of neural tube defects).