homocysteine

HomocysteineHomocysteine

Tapeshwar Yadav(Lecturer)BMLT, DNHE, M.Sc. Medical Biochemistry

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IntroductionIntroductionHomocysteineHomocysteineSulfur-containing amino acid

Three forms in plasma/serum

Sulfuration

An intermediate product of methionine metabolism

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MethionineMethionine


CystathionineCystathionine

CysteineCysteine

Cystathionine synthase

Cystathioninase

Vitamin BVitamin B66


Methyl transferase

Homocysteine metabolismHomocysteine metabolism

S-Adenosyl methionine

S-Adnosyl homocysteine

Acceptor

Methylated acceptor

【 Remethylation 】

【 Trans-sulfuration 】

B12

Methyl B12

Methyl THF

THF

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Increase Homocysteine concentration Increase Homocysteine concentration MethionineMethionine


CystahionineCystahionine

CysteineCysteine

Cystathionine synthase

Cystathioninase



Methyl transferase

【 Nutritional deficiencies, Life style , Drugs , Some diseases 】

【 Genetic deficiency 】

HomocysteinuriasHomocysteinurias Normal levels :Normal levels :

– In serum = 13-18 µmol/LIn serum = 13-18 µmol/L– In plasma = 10- 15 µmol/LIn plasma = 10- 15 µmol/L

In paediatric patients – 3.7-10.3 µmol/LIn paediatric patients – 3.7-10.3 µmol/L In diseases increased upto 50-100 times.In diseases increased upto 50-100 times. Moderate rise in aged persons, BModerate rise in aged persons, B1212 or B or B6 6

deficiency, tobacco smokers, alcoholics and deficiency, tobacco smokers, alcoholics and in hypothyriodism.in hypothyriodism.

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Substantial rise in congenital diseases Substantial rise in congenital diseases large large amounts amounts Urine. Urine.

In plasmaIn plasma

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Homocysteine -SH

Homocystine –S-S-

Normally absent in urine

If present i.e. in -S-S- form

Homocysteinuria Type I :Homocysteinuria Type I : Enzyme deficiency is Cystathionine Enzyme deficiency is Cystathionine ββ--

Synthase.Synthase. Increased methionine & homocysteine in Increased methionine & homocysteine in

Plasma Plasma cysteine↓ cysteine↓ Increased methionine & homocystine in Increased methionine & homocystine in

urine.urine.

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Symptoms :Symptoms : Mental retardationMental retardation Charley chaplin gaitCharley chaplin gait Skeletal deformitiesSkeletal deformities EyesEyes

– Ectopia lentisEctopia lentis– MyopiaMyopia– Glaucoma.Glaucoma.

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Homocysteine Homocysteine activation of Hageman factor activation of Hageman factor ↑↑platelet adhesiveness platelet adhesiveness life threatening life threatening intravascular thrombosis.intravascular thrombosis.

Cyanide nitroprusside test +ve (urine)Cyanide nitroprusside test +ve (urine) Urinary homocysteine > 300 mg/24 hours.Urinary homocysteine > 300 mg/24 hours. Plasma homocysteine & methionine Plasma homocysteine & methionine ↑.↑. Treatment : Treatment : Diet low in methionine, rich in Diet low in methionine, rich in

cysteine. cysteine. Some times affinity of apoenzyme to coenzyme Some times affinity of apoenzyme to coenzyme

↓. Large quantities of PLP coenzyme.↓. Large quantities of PLP coenzyme.

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Homocysteinuria II :Homocysteinuria II : Deficiency of NDeficiency of N55-N-N1010 methylene THF reductase. methylene THF reductase. ↓↓Methionine synthesis.Methionine synthesis. ↑↑Homocystine in urine.Homocystine in urine. Behavioral changes, vascular abnormalities.Behavioral changes, vascular abnormalities.Treatment : Treatment : Folate supplementation.Folate supplementation.

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Homocysteinuria III :Homocysteinuria III : Low NLow N55 methyl THF HMT. methyl THF HMT. Inability to synthesize Methyl cobalamine.Inability to synthesize Methyl cobalamine.Homocysteinuria IV :Homocysteinuria IV : Defective intestinal absorption of cobalamin.Defective intestinal absorption of cobalamin. ↑↑Homocysteine &↓MethionineHomocysteine &↓Methionine Urine contains homocystine.Urine contains homocystine.

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Cystathioninuria:Cystathioninuria: Deficiency of Cystathioninase.Deficiency of Cystathioninase. AR; Anemia, Thrombocytopenia, AR; Anemia, Thrombocytopenia,

Endocrinopathies.Endocrinopathies. Acquired Acquired BB66 deficiency.deficiency. In liver diseases and after In liver diseases and after ThyroxineThyroxine

administration.administration.Diagnosis : Diagnosis : Cyanide nitroprusside test –ve ; Cyanide nitroprusside test –ve ;

cystathionine in urine.cystathionine in urine.Treatment : Treatment : BB6 6 administration (200-400mg/day)administration (200-400mg/day)

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Acquired hyperhomocysteinemias :Acquired hyperhomocysteinemias : Nutritional deficiency of vitamin BNutritional deficiency of vitamin B1212, Folate & , Folate &

BB66.. Metabolic-chronic renal diseases, Metabolic-chronic renal diseases,

hypothyroidism ,drug induced-folate, Bhypothyroidism ,drug induced-folate, B1212, B, B66 antagonists.antagonists.

Estrogen antagonists, nitric oxide antagonists.Estrogen antagonists, nitric oxide antagonists.

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Homocysteine role as cardiac marker :Homocysteine role as cardiac marker :HomocysteineHomocysteine Lysyl residues of collagenLysyl residues of collagen

Interferes collagen crosslinkingInterferes collagen crosslinking

Homocysteine thiolactoneHomocysteine thiolactone

Thiolates LDL particlesThiolates LDL particles

AggregateAggregate

Endocytosed by macrophagesEndocytosed by macrophages

↑↑ed tendency for atherogenesised tendency for atherogenesis 14

Providing adequate quantities of B6, B12, FA HC – N.Maternal Hyperhomocysteinemia NTD in fetus.

Refsum & collegues :Refsum & collegues :1)1) Measurement of tHcy in general population to screen for Measurement of tHcy in general population to screen for

CHD risk is not recommended.CHD risk is not recommended.2)2) In young CHD patients (<40 years) tHcy measured In young CHD patients (<40 years) tHcy measured to to

exclude homocystinuria.exclude homocystinuria.3)3) In patients with CHD & at risk of CHD, a high tHcy conc In patients with CHD & at risk of CHD, a high tHcy conc

should be used as a prognostic factor for CHD.should be used as a prognostic factor for CHD.4)4) CHD pts with tHcy > 15 µmol/L CHD pts with tHcy > 15 µmol/L high risk group. high risk group. Important Important to follow a healthy life style and to receive to follow a healthy life style and to receive

optimal treatments for known casual risk factor.optimal treatments for known casual risk factor.1)1) ↑↑tHcy with low tHcy with low BB12 12 & & BB66 conc conc handled as a potential handled as a potential

vitamin deficiencies. Other causes of ↑ tHcy should be vitamin deficiencies. Other causes of ↑ tHcy should be considered.considered.

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Homocysteine :Homocysteine : Promotes oxidant injury to vascular Promotes oxidant injury to vascular

endothelium.endothelium. Impairs endothelium dependant relaxation.Impairs endothelium dependant relaxation. Alters coagulant properties of blood.Alters coagulant properties of blood. ↑↑tHcy tHcy release Superoxide radicals release Superoxide radicals

Atherogenesis.Atherogenesis. ↓ ↓bioavailability of NO bioavailability of NO ↓endothelial ↓endothelial

vasodilation function.vasodilation function.

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Prevalance :Prevalance : Gen pop Gen pop 5-10 % 5-10 % Elderly Elderly 30-40 % 30-40 % Pts with vascular disease Pts with vascular disease 20-40 % 20-40 %↑↑tHcy associated with tHcy associated with 1)1) OsteoporosisOsteoporosis2)2) Cognitive impairment & decline.Cognitive impairment & decline.3)3) Chronic kidney disease.Chronic kidney disease.

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Lab assesment of tHcy :Lab assesment of tHcy : Pre-treatment of serum or plasma with reducing Pre-treatment of serum or plasma with reducing

agent. Dithioerythreitol, mercaptoethanol, tributyl agent. Dithioerythreitol, mercaptoethanol, tributyl phosphine.phosphine.

Immuno assys :Immuno assys : Flourescence polarisation immuno assay.Flourescence polarisation immuno assay.Chromatographic :Chromatographic : AA analysisAA analysis HPLCHPLC Capillary electrophoresis with flourescence Capillary electrophoresis with flourescence

detection GC-MS.detection GC-MS.18

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StudiesStudiesPlasma homocysteine levels is an independent risk factor for cardiovascular disease.

（ Kuller., 1998;Hankey et al., 1999;Keebler et al, 2002）Plasma homocysteine levels is normally < or = 12 micromol/L, but when it elevated has many deleterious cardiovascular effects. （ Warren., 2002 ）High homocysteine levels in plasma promotes oxidant injury to the vascular endothelium, and it damage leads to platelet activation and thrombus formation . （ Loscalzo et al., 1998;Maxwal., 2000 ）

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StudiesStudies

Vitamin B6 deficiency is an increase in homocysteine plasma concentration and is associated to an increment in cardiovascular diseases. （ Tottes et al., 2001 ）

High plasma homocysteine levels is due to genetic defects in the enzymes that control homocysteine metabolism, and nutritional deficienciency in vitamin B6. （ Blanco et al., 2001）

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Thank youfor your

attention.

homocysteine

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