Transcript Hyperhomocystinaemia

Hyperhomocyst(e)inemia and
Thrombophilia
• A major point of consensus was that
no causal role of hyperhomocyst(
• e)inemia in venous or arterial
thrombosis is not yet established
• Homocysteine is a non–protein-forming
sulfhydryl amino acid
• Dietary methionine Homocysteine
(Intracellular demethylation)
• Homocysteine methionine (remethylation)
• is derived from the reduction of
• 5,10-methylene-tetrahydrofolate
Methyltetrahydrofolate (MTHFR).
• Methionine excess  homocysteine may
enter the transsulfuration pathway.
• Hyperhomocystinemia :marked increase
in atherothrombotic CVD and VTE.
• 25% : vascular occlusive event by age 16
year & 50% by age 29 years.
• Of these events, 32% are CVA, 4% are
MI , 11% are peripheral arterial
• occlusions, and 51% are VTEs.
• The event rate is reduced by vitamin
therapy in B6-responsive individuals.
• The gene for MTHFR is located on
chromosomal region 1p36.
• Thermolabile mutant.
• 12% of the population in the United
States is homozygous
• Estrogen-containing medications result
in lower plasma homocysteine levels
New Concepts in
Congenital Thrombophilia
Galila Zaher
(November 1999)
Congenital thrombophilia
Inherited thrombophilia can be defined
as a
genetically determined tendency to
venous
thromboembolism.
Genetic risk factors are now identified in
3050% of affected individuals.
Table 1. Risk factors for inherited thrombophilia: prevalence and
relative risk for venous theombosis
Risk factor
Year
describe
d
Prevalence in
the general
population
(%)
Relativ
e risk
for
VTE*
Antithrombin deficiency
Protein C deficiency
Protein S delivery (free PS)
APC resistance
Hyperhomocysteinaemia
Factor VIII levels > 150 IU/dl
Prothrombin gene G20210A
variant
1965
1981
1984
1993
1994
1995
1996
0.181
0.24
1.35
<156***
53
113
2.33
5.03**
6.53
2.45
6.63
2.53
4.83
2.83
Hyperhomocystinaemia
Homocysteine is a sulphur containing A
A.
It is derived from methionine EAA.
Homocysteine metabolism:
MTHFR
Re methylation pathway
C s
Trans sulphuration pathway
Trans methylation pathway
Hyperhomocystinaemia
Interest in homocysteine as a risk factor
for
vascular disease came from the early
observations that such diseases are
common
in cases of classical homocystinuria.
Hyperhomocystinaemia
Neural tube defects (NTPs)
Arterial vascular disease
Venous thromboembolism
Hyperhomocystinaemia
NTDs.
Neuronal tube defects occur in 1/1000 birth in USA
It has a complex trait interacting with
environmental factors.
Homozygousity for TL-MTHFR has been clearly
shown to be a risk factor for spina bifida in 12% o
the cases.
Pre conceptional supplementation of folic acid
could prevent
up to 70% of NDTs
Folic acid 4 mg reduces the recurrence of NTDs
Hyperhomocystinaemia
Arterial vascular disease
Potential mechanisms
Oxidative damage to endothelial cells.
Enhanced plt adhesion to endothelial cells
Enhanced plt aggregation
Plt accumulation and the formation of plt rich
thrombous
Inhibition of TM expression
Increased procoagulant activity and reduced
natural
Anticoagulant
Hyperhomocystinaemia
Arterial vascular disease
Metanalysis of published studies revealed
that
elevation in total plasma homocysteine were
found to be an independent risk factor for all
forms of arterial vascular disease.
(Perry Advances in Haem. 1999)
Hyperhomocystenaemia
Arterial vascular disease
* 15-40% of patients with conorary, cerebral
of peripheral arterial disease have high
plasma level of homocysteine > 20 
moL/L.
The odd ratio for IHD is 1.4 for every 5  *
moL/L more than homocysteine median
fasting adult males.
C677T mutation is a major cause of mild *
hyperhomocystinenia, but the mutation
per se does not increase cvs disease risk
Hyperhomocystinaemia
venouss thromboembolism
There is accumulating data to suggest that
hyperhomocystinemia is a risk factor for VTE
that is independent of coexisting abnormalities
of the
naturally occurring
Anticoagulant.
Homozygosity TL-MTHFR together
with low folate level confers moderate risk
factor.
Hyperhomocystinaemia defined as plasma
level
Hyperhomcystinaemia
Laboratory evaluation
Intra individual variability
Inter Laboratory variability
ELISA
HPLC
EIA
Hyperhomocystinaemia
Laboratory evaluation
There is an urgent need to improve
analytical
impression and decrease the difference
among
methods.
An ideal homocysteine reference range
based
on targeting subject with highest serum
Hyperhomocystinaemia
Laboratory evaluation
Fasting total plasma homocysteine
level
Methionin loading dose.
Serum Folate and B12 Pevel
C677T PCR
Hyperhomocystinaemia
Lowering vit dose
Plasma ThCY response to folic acid and
Pyridoxin hydrochlorid
The optimal homocysteine lowering vitamin
dose
and target ThCY are
currently unknown.
Proposed does.
500-650 g Folic acid
100 mg Pyridoxin
0.4 mg.
B 12
Issues to be addressed
What is the minimum dose of folic acid to
prevent
NTDs?
Would grain fortification adapted in USA
reduce
NTDs, protects against arterial vascular
disease?
What is (are) the best test (s) to evalaute
Concluding Remarks
Folate supplementation reduces the .1
occurance and recurrence of NTDs.
Elevated fasting plasma homocysteine is .2
an independent risk factor for all forms of
arterial vascular disease.
Concluding Remarks
(Continue)
Homozygonosity for TL-MTHFR is not a .3
significant risk factor for VTE per se
There is currently no strong argument to .4
include MTHFR C677T genotyping during
routine thrombophilia screen.
Combination of hypercystinaemia and .5
FvL abnormality significantly increase
the risk for VTE.
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