< Concept analysis >
Most high homocysteine due to cystathionine β synthase (cystathionine β-synthase, CBS) loss of function caused by multiple organ disease, manifested as multiple thromboembolism, mental retardation , crystal ectopic , Zhi Zhi Guo long.
< Foreword >
Homocysteine also known as homocysteine (Homocysteine, Hcy), is the intermediate metabolite of methionine . Currently found that high homocysteine is mainly because the encoding methylenetetrahydrofolate reductase (MTHFR), cystathionine synthase (CBS) and other gene mutation , causing enzyme defect or caused by reduced activity . Normal fasting plasma homocysteine concentration was 5 ~ 15μmol / L, according to AHA classification , 15 ~ 30 μmol / L were mild , 30 ~ 100μmol / L , moderate and severe ,> 100μmol / L severe. Methionine > 400μmol / L can cause toxicity.
Studies have shown that 10% of coronary heart disease and elevated homocysteine , can cause mild to moderately elevated risk of death from cardiovascular disease increased 4-6 times , so now the blood homocysteine disorders as atherosclerosis and coronary heart disease an independent risk factor.
< Etiology >
The disease mainly there are three common biochemical defect type :
Deficient
The main reason
Cystathionine β
Synthase
Deficient
( Synthase deficiency type )
The most common type
Due to cystathionine synthase (CBS) deficiency (cystathionine beta synthase deficiency), homocysteine into cystathionine pathway is blocked → homocysteine can be metabolized in the blood , urine large accumulation homocysteine and methionine increased blood clotting factor → further action , as well as affect protein metabolism and collagen fiber structure → causing lens dislocation , osteoporosis , fractures, mental retardation , multiple vascular occlusion , arterial thrombosis
[Note] Vitamin B6 is cystathionine synthase (CBS) coenzyme
Methylenetetrahydrofolate -
Homocysteine A
Transferase enzyme deficiency type
Because homocysteine into methionine metabolic pathway disorder . Methyltransferase activity itself is normal, but it is a coenzyme ( vitamin B12) deficiencies. Blood and urine increased homocysteine , methionine in the blood is not increased ; blood and urine increased cystathionine
[Note] Vitamin B12 is a coenzyme methyl transferase
N5, N10- methylenetetrahydrofolate
Folate reductase deficiency type
( Reductase deficiency type )
Methylenetetrahydrofolate reductase deficiency (MTHFR), can not lead to methylation of homocysteine in blood and urine homocysteine increased. Clinical manifestations are dominated by the nervous system
< Charts > homocysteine metabolism have two paths :
Homocysteine → ( from 5 - methyl- tetrahydrofolate as the methyl donor , the methyl transferase catalyzed themselves reduced folate , vitamin B12 when this phase requires coenzyme ) → methionine → S- adenosylmethionine → S- adenosyl homocysteine .
Homocysteine → cystathionine synthase in (CBS) + Vitamin B6 Coenzyme assisted by condensation with serine to form cystathionine → → cysteine + α keto acid .
< Pathological changes and clinical manifestations >
Typical symptoms seen in CBS -deficient . Normal newborn infants , about six months of onset . The main symptoms are skeletal abnormalities , lens dislocation , any part of the thrombosis, mental retardation , convulsions , etc.
Position
Pathological changes
Clinical
Arteries and veins
Intimal fibrosis, large vascular media thinning , elastic fiber failure , stenosis or occlusion ; thrombosis . Hcy can promote LDL oxidation extensive atherosclerotic plaque and thrombosis (extensive atheroma formation and intra vascular thrombosis
Brain
Neuronal loss , white matter demyelination ; activation of the clotting factor Ⅻ, Ⅴ, change the proteoglycan structure → → dural sinus thrombosis and cerebral embolism caused by softening of the brain cavernous obvious neurological symptoms , including the emergence of mental disorders (Mental retardation ) , convulsions (Seizures), CVA, psychiatric symptoms (Psychiatric disease)
Kidney
Epithelial cell swelling homocystinuria ; opaque brown staghorn cystine calculi (Cystine stones)
Hair, striated muscle
"Z" band broke filaments structural disorder facial flushing (Flush across the cheeks), marbled skin , the skin is thin, sparse hair easily broken, myopathy
Eye
The most common change was a small strip abnormal lens dislocation (ectopia lentis), glaucoma (Glaucoma), optic atrophy and retinal detachment (Optic atrophy), myopia (Myopia)
Skeleton
Form bad , osteoporosis
Tall, thin, slender body and limbs and fingers and toes (Tall, thin build, slender limbs (dolichostenomelia); X-ray: a double concave dorsal vertebrae , scoliosis (scoliosis) and other performance. Empty concave foot (High-arched feet (pes cavus)), X -type legs (Knock-knees (genu valgum)), pectus excavatum (Pectus excavatum), chicken Breast (Pectus carinatum)
< Treatment >
No method can be cured , however , CBS deficiency can be the use of large doses of vitamin B6 (treated using high doses of vitamin B6), combined vitamin B12, folic acid (folic acid) and betaine (N, N, N- trimethylglycine, Betaine) treatment ( Note 1 ) , and with diet therapy ( Note 2 ) , the use of low methionine diet (Low Methionine diet), added cysteine (L-cysteine). Regular monitoring of blood and urine methionine content of cysteine values.
[Note 1] Betaine can promote homocysteine into methionine to reduce homocysteine concentrations (reduce concentrations of homocysteine by promoting the conversion of homocysteine back to methionine).
[Note 2] limit intake of methionine containing high protein foods and high-protein foods such as meat , fish, shellfish , poultry, eggs, milk , cheese , beans, nuts and so on. Adequate intake of vegetables , fruits . Eating low methionine special milk . More stringent controls , the degree of sequelae more light .
If stones , water should be added to ensure that the daily urine output 4L to reduce urinary cystine concentration . Oral NaHCO3 alkaline urine ; bedtime Acetazolamide in order to increase the solubility of cystine in the urine .
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