Homocysteine

Dr. Yousef Elshrek

Homocysteine

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

•

methionine

• 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

• 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.

• 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

• 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

• 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).

• 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.

• 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.

• 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

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).

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.

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.

• 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

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

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

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).

• 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

• 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.

•

• 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

• 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

• 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.

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

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

• 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).

• 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.

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.

• 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

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.

• 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.

• 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

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.

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.

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

• 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

RDA for Vitamins B6, B12 and Folate

• Vitamin B6 2 mg

• Vitamin B12 6 mcg

• Folate 400 mcg

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