1. Homocysteine
Dr. Yousef Elshrek

2. Homocysteine
• Homocysteine is an amino acid methionine
that is produced by the body, usually as a
byproduct of consuming meat.
•
methionine

3. • Methionine is one of an essential amino acids --
compounds that the body needs but is unable to
make by its own biochemical processes.
• The body's need for methionine must be met from
dietary sources.
• Methionine is converted to other biological
compounds such as
1. ethanolamine.
2. homocysteine,
3. cysteine,
4. carnitine,
5. taurine
6. and lecithin. ethanolamine

4. • Ethanolamine (EA) deserves special
attention as a component of
phospholipids and a compound
structurally similar to ethanol.
• As a natural metabolite with very low
toxicity, EA decreases the
manifestation of alcohol in- toxication
in rats and the duration of narcotic
sleep caused by alcohol.

5. • S-adenosyl methionine (SAM) participates in
phosphatidyl ethanolamine transmethylation
during phosphatidyl choline bio- synthesis.
• Methylation processes in the brain are
believed to contribute to the development of
con-vulsions in many neurological diseases,
including chronic alcoholization and the
abstinence syndrome

6. • Brain lipids are studied in rats with chronic
alcohol intoxication after injection of S-
adenosyl methionine, ethanolamine, and their
combination.
• The levels of total lipids, phospholipids, and
cardiolipin are increased and those of
sphyngomyelin and cerebrosides-III
decreased after a 14-day inhalation of
ethanol.
• Combined administration of S-adenosyl
methionine and ethanolamine in chronic
alcoholization eliminated ethanol-induced
shifts in concentrations of phospho - and
glycolipid fractions in rat brain

7. • carnitine: In many studies found that the heart carnitine
levels of male, weanling Sprague-Dawley rats fed nutritionally
adequate liquid diets with 35% of calories as ethanol for 3
weeks were not different from control or pair-fed rats
(Experiment 1).
•
• When ethanol was given as 30% of energy in combination
with a diet deficient in methionine and choline, and the
feeding period was extended to 5 weeks, heart carnitine
levels were significantly affected (Experiment 2).

8. • Carnitine levels in whole heart
homogenates of the methionine and
choline deficient chronic ethanol-fed group
were 2.14±0.74 μmoles per g dry wt.
significantly lower (p<0.05) than deficient
controls, 3.08±0.85 μmoles per g dry wt.
• The study concluded that a methionine
and choline deficient diet exacerbates the
effects of alcohol on methyl-group
metabolism so as to produce decrements
in heart carnitine not seen when alcohol is
given with an adequate diet.

9. • Taurine is a sulfur amino acid like methionine, cystine,
cysteine and homocysteine.
• It is a lesser-known amino acid because it is not
incorporated into the structural building blocks of
protein.
• Yet taurine is an essential amino acid in pre-term and
newborn infants of humans and many other species.
• Adults can synthesize their own taurine, yet are probably
dependent in part on dietary taurine.
• Taurine is abundant in the brain, heart, breast,
gallbladder and kidney and has important roles in health
and disease in these organs.

10. • Lecithin:- it acts as a wetting, stabilizing
agent and a choline enrichment carrier, helps in
emulsifications and encapsulation, and is a good
dispersing agent.
• It can be used in manufacture of intravenous fat
infusions and for therapeutic use

11. Biochemical links between Methionine
and Homocysteine
• The amino acid homocysteine is synthesized in a
series of steps beginning with the conversion of
methionine to S-adenosylmethionine (SAM).
•
S-adenosylmethionine (SAM).

13. High-Protein Diet May Raise Serum
Homocysteine Levels
• A diet high in protein has been shown to directly increase the
amount of homocysteine in the body.
• If we looked at the difference in serum homocysteine levels in
subjects given a protein-rich diet versus a relatively protein-poor
diet.
• The researchers found that daily ingestion of high amounts of
protein did in fact increase homocysteine levels.
• While levels were increased after meals, they returned to
normal when sampled just before breakfast.
• These researchers also found a direct relationship between
methionine intake and serum homocysteine.

14. Methionine, Homocysteine, B
Vitamins
• Paradoxically, studies of the consequences of high-
protein weight loss diets showed a reduction in
homocysteine concentrations despite the high intake
of protein-derived methionine.
• Swedish researchers published a 2002 study in "The
American Journal of Clinical Nutrition" that examined
the effects of high protein and methionine intake in
obese subjects.
• Their research found a 25 percent decrease in
homocysteine levels in the high-protein diet group
compared with the low-protein diet subjects.

15. • The likely explanation for this unexpected result lies
in the influence of B vitamins -- especially B6 -- on
the clearance of homocysteine from the blood.
• A direct consequence of B-complex deficiency is
higher homocysteine levels.
• Vitamin B12 assists in the recycling of homocysteine
back to methionine.
• B6 is crucial to the conversion of homocysteine to
cysteine.
• As a consequence, diets high in protein -- yet rich in
B vitamins -- do not lead to high serum
homocysteine

16. Homocysteine metabolism
Methionine
Homocysteine
Cysteine
meat, eggs, milk, cheese,
white flour, canned foods
and highly processed
foods.
Methyl transferase
• Vitamin
B12
• Folic
Acid
Cystathionine synthase
• Vitamin
B 6
Circulation. 1999;99:178-182

17. Increase homocysteine concentration
Methionine
Homocysteine
Cysteine
Methyl transferase
Cystathionine synthase
Genetics: altered
enzyme activity of HCy
related pathways
【 nutritional deficiencies,
life style , drugs ,
some diseases 】
• Vitamin
B 6
Family history: of
heart disease, stroke,
cancr,Alezheimer’s
disease, diabetes
• Vitamin
B12
• Folic
Acid

18. Medical Benefits of Lowering
Methionine Intake
• Methionine is necessary for good health, but its role in
homocysteine production has harmful repercussions.
• High homocysteine levels are linked to alterations of
blood vessels that may contribute to cardiovascular
disease.
Experiments on arteries of both animals and humans
with an elevated level of homocysteine showed that
homocysteine level in blood is an independent risk
factor for atherosclerotic vascular disease affecting the
coronary (arteries supplying the heart), cerebral
(arteries supplying the brain) and peripheral arteries
(supplying the rest of the body).

19. • A paper published in the journal "Alternative Medicine
Review" in 2003 linked the negative effects of
homocysteine and its metabolites on blood vessels in
the brain to Alzheimer's disease
• People with the highest levels of blood homocysteine
had almost double the risk of Alzheimer's and other
dementia as compared to people with lower blood
homocysteine.
• Increase of 5 micromoles of homocysteine per liter of
blood increased the risk of Alzheimer's Disease by 40%.
• The mechanism linking Hcy and Alzheimer’s disease is
poorly understood, it is possible that Hcy is toxic to
brain cells, possibly by excessive stimulation, resulting
in neuronal damage due to CNS ischemia

20. • Lowering methionine intake may reduce the risks of
cardiovascular disease.
• How Homocysteine effects CVD
• Homocysteine is one of many damaging agents to
endothelial cells
• LDL and platelets invade
• Platelets secrete chemoattractants for monocytes
• PDGF - Platelet derived growth factor stimulates
smooth muscle proliferation and thickening of the
tunica media.
• Smooth muscle cells from the tunica media invade
the tunica intima.
• Monocytes invade and are activated to
macrophages/scavenger cells.
•

21. • Smooth muscle cells and macrophages ingest LDL
• Foam cells/Fatty streaks
• The high amounts of cholesterol ester consumed
will precipitate into crystalline deposits.
• Deposits calcify and become rough stimulating
clot formation creating a fibrous plaque.
• Narrows the lumen of the vessels, restricting
blood flow

22. • Animal studies suggest that methionine-
deficient diets increase lifespan.
• A 2005 study of rats fed methionine-deficient
diets was published in the journal "Aging Cell.“
• The researchers found the rats had lower levels
of blood glucose, thyroid hormone and other
markers associated with increased longevity.
• Maintaining a proper balance of protein-derived
methionine and B-complex vitamins may extend
the life of humans as well

24. • Abnormally raised insulin seen in most
diabetics stops the body from lowering and
maintaining a healthier homocysteine level.
• One third of the diabetic patients had
elevated blood Homocysteine
• Type 2 diabetic patients with elevated
homocysteine levels are nearly 200% more
likely to die from a heart attack within 5
years than those with normal Homocysteine
levels
Homocysteine & Diabetes
Vasc Health Risk Manag. 2010; 6: 327–332.

25. Homocysteine Levels May Be Related
to Osteoporosis
• An increased homocysteine level appears to
be a strong and independent risk factor for
osteoporotic fractures in older men and
women
• high serum homocysteine concentration may
weaken bone by interfering with collagen
cross-linking, thereby increasing the risk of
osteoporotic fracture

26. Homocysteine & Pregnancy
Complication
• Women who have higher levels of homocysteine
are more likely to have delivered prematurely,
had recurrent abortions and had offspring with
low birth weights.
• Folic acid supplements decrease homocysteine
levels during pregnancy and substantially reduce
the risk of central nervous system
malformations
• women with high levels of homocysteine have a
much higher risk of developing preeclampsia

28. • Clinical
• While the metabolic defect is present at birth,
initial symptoms of homocystinuria usually have
onset later in infancy and childhood.
• Developmental delay may be the first sign and is
a harbinger of mental retardation, but is not
obligate.
• An early and distinctive finding is dislocation of
the lens of the eye (ectopialentis).

29. • Patients are at high
risk for developing
thromboembolism that
may occur at any age.
• These may lead to
stroke, seizures,
permanent neurologic
sequela and death.
• Increased clotting
ability makes surgery a
risk.
• Osteoporosis is a long-
term complication of
homocystinuria.

30. Testing
• Newborn screening of a dried blood spot
using tandem mass spectrometry reveals
elevated levels of methionine, which
should prompt testing plasma for amino
acids, including homocysteine.
• Elevated methionine and homocysteine in
plasma indicate CBS deficiency, while an
isolated increase in methionine suggests
hepatic methionine adenosyltransferase
deficiency.

31. • In affected patients, the presence of
homocysteine in the urine is a consistent
finding, especially after early infancy.
• CBS enzyme activity can be measured in many
tissues, including fibroblasts, lymphocytes, liver,
amniocytes, and chorionic villi (biopsy or
cultured cells).
• Deficient enzyme activity may be followed with
DNA mutation analysis for the several known
mutations in the CBS gene

32. Treatment
• Treatment of CBS deficiency usually begins with a trial of oral
vitamin B6 (pyridoxine) supplementation, with daily
measurement of plasma amino acids.
• CBS requires pyridoxine as a coenzyme for enzymatic activity.
• Overall, about 25% of patients respond to large doses of
pyridoxine, although the percentage may be lower for patients
identified through newborn screening.

33. • This pyridoxine response usually coincides
with the presence of some residual enzyme
activity.
• Dietary restriction of Methionine in
conjunction with Cystine supplementation
reverses the biochemical abnormalities to
some extent and appears to reduce the
clinical symptoms.
• Special formulas are available commercially,
but the diet is difficult to maintain long term.

34. • In an attempt to decrease Homocysteine levels,
folic acid, and betaine can be supplemented to
induce recycling of this amino acid to Methionine
for alternate metabolism.
• Vitamin B12 (cobalamin) may also be helpful.
• Because the diagnosis and therapy of
Homocystinuria is complex, the pediatrician is
advised to manage the patient in close
collaboration with a consulting pediatric
metabolic disease specialist.
• It is recommended that parents travel with a
letter of treatment guidelines from the patient’s
physician

35. Inheritance
• This disorder most often follows an autosomal recessive
inheritance pattern.
• With recessive disorders affected patients usually have
two copies of a disease gene (or mutation) in order to
show symptoms.
• People with only one copy of the disease gene (called
carriers) generally do not show signs or symptoms of the
condition but can pass the disease gene to their children.
• When both parents are carriers of the disease gene for a
particular disorder, there is a 25% chance with each
pregnancy that they will have a child affected with the
disorder.
• As with all genetic diseases, genetic counseling may be
appropriate to help families understand recurrence risks
and ensure that they receive proper evaluation and care.

36. Homocysteine and Nutrition:
The Vitamin Connection
• Screening for HCY may indirectly assess a patient’s
vitamin B6, B12 and folate status, thus offering a
useful window into the patient’s nutrition profile.
• Total homocysteine measurements are now
recommended to screen for vitamin deficiency in both
the general and high risk populations.
• Homocysteine may, in fact, be a more sensitive
marker of Vitamin B12 , B6 or folate deficiency and…
may precede deficiency of circulating vitamins.

37. Vitamins and Food sources
• Folic acid - Green leafy vegetables (e.g. spinach,
broccoli), legumes (e.g. lentils, chick peas, lima
beans), orange
• Vitamin B6 - Meat, poultry, fish, green leafy
vegetables, legumes, seeds, potatoes, cantaloupe,
milk, egg yolks, cereals, grains, wheat, wheat
germ.
• Vitamin B12 - Beef, poultry, fish (particularly crab,
oyster, salmon and herring), liver, kidney, soy, fruit
juice, dairy products, egg yolks, fortified cereals,
breads

38. • Folic acid fortification of enriched
grain products appears to have
resulted in a decline in stroke and
ischemic heart disease deaths.
• There has been evidence of three-fold
acceleration in the decline of stroke
related mortality that has been
temporarily related to folic acid
fortification.
American Journal of Clinical Nutrition, Vol. 86, No. 5, 1563S-1568S, November 2007

39. RDA for Vitamins B6, B12 and
Folate
• Vitamin B6 2 mg
• Vitamin B12 6 mcg
• Folate 400 mcg

40. The Final word
• The lower the homocysteine level, the lower
the risk of developing coronary artery disease
and suffering fatal heart attacks and strokes .
• Your Homocysteine level is the best single
indicator of whether you are going to live a
long and healthy life, or die young.
• A high homocysteine level is a greater risk
factor for many health problems
• Without any doubt, the demand for plasma
homocysteine testing will increase in the
coming months and years, perhaps explosively