Homocysteine: An Overlooked Biomarker in Clinical Medicine

Homocysteine – The “H factor”
Dr. Furquan Alam
MD (Biochemistry)
Assistant Professor
Glocal Medical College, SSH & RC, Saharanpur
An Overlooked Biomarker in
Clinical Medicine

Why it is
important to
discuss?
07 March 2017 Dr. Furquan Alam 2

• High levels of homocysteine, or a high "H
Score," predicts the risk of more than 100
diseases and medical conditions including
CVD, CVA, Diabetes, Renal Disease etc.
• Elevated Plasma Homocysteine is an
important, Strong, Graded and
Modifiable Risk Factor.
• ↑ Hcy at baseline also Predicts higher long
term Mortality.
07 March 2017
Dr. Furquan Alam 4

Factors affecting blood Homocysteine Level

What is
homocysteine?

Introduction
• Homocysteine (Hcy), a sulphur containing amino acid
with a molecular weight of 135.2 Dalton.
• Derived from Methionine
• First isolated from a urinary bladder stone in 1933 by
Vincent du Vigneaud.
• Later Vincent du Vigneaud received the Nobel Prize in
chemistry in 1955.

9
Homocysteine
Three forms in plasma/serum
Sulfuration
07 March 2017 Dr. Furquan Alam

• Varying forms
• 1% free
• 70-80% bound to albumin via a disulfide link
• 20-30% either as a homocysteine dimer or a
cysteine-homocysteine-mixed disulfide.
* The type(s) of species responsible for the CVD
pathology have yet to be determined.

Homocysteine
• Normal levels :
• In serum: 13-18 µmol/L
• In plasma: 10- 15 µmol/L
• In pediatric patients: 3.7-10.3 µmol/L
• Desirable Serum Level: <10 µmol/lit, preferably between
7-8 µmol/lit.
 Hyperhomocysteinemia:
Mild
• 15 – 30
µmol/lit
Moderate
• 30 -100
µmol/lit
Severe
• >100
µmol/lit

Hyperhomocysteinemia

Methionine
Homocysteine
Cystathionine
Cysteine
Cystathionine synthase
Cystathioninase
Vitamin B6
Vitamin B6
Methyl transferase
Homocysteine metabolism
S-Adenosyl
methionine
S-Adenosyl
homocysteine
Acceptor
Methylated
acceptor
【Remethylation】
【Trans-sulfuration】
B12
Methyl B12
Methyl THF
THF

Increase Homocysteine concentration
Methionine
Homocysteine
Cystathionine
Cysteine
Cystathionine synthase
Cystathioninase
Vitamin B6
Vitamin B6
Methyl transferase
【Nutritional deficiencies,
Life style , Drugs ,
Some diseases 】
【Genetic deficiency】

Etiology of Hyperhomocysteinemia
• Genetic mutations
• Nutritional deficiencies
• Disease states
• Drugs

Genetic Mutations
5-methyleneterahydrofolate reductase (MTHFR)
polymorphism due to a point mutation on chromosome 1.
Prevalence MTHFR
15% in European, Middle Eastern and Japanese
1.4% or less in African Americans.
Mild to moderate condition
Higher risk of neural tube defects and pregnancy loss
Mother with the MTHFR mutation who have normal
homocysteine levels are not at increased risk for clots.

Nutritional deficiencies
• Folate deficiency
• Vitamin B12 (Cobalamine) deficiency
• Vitamin B6 (Pyridoxine) deficiency

Disease states
• Cystathione β-synthase deficiency
• Homocysteinuria
• Methionine synthase deficiency
* Both are rare autosomal recessive disorders that are
correlated with Hyperhomocysteinemia and vascular
thrombosis.
• Chronic renal failure regardless of etiology, duration,
or type of dialysis
• Severe psoriasis
• Possibly through increased cell turnover
• Pernicious anemia
• Cobalamine deficiency

Drugs That Raise Homocysteine Levels
• A number of prescription drugs and natural compounds
can elevate blood levels of homocysteine by interfering
with folate absorption or metabolism of homocysteine.
Caffeine Niacin
Cholestyramine Nitrous oxide
Colestipol Pemetrexed
Fenofibrate Phenytoin
Levodopa Pyrimethamine
Metformin Sulfasalazine
Methotrexate Carbamazepine

Drugs
• Cholestyramine (reduces cholesterol in blood)
• Impairs folate absorption
• Methotrexate (treatment of psoriasis)
• Depletes folate metabolites
• Anti-epileptics (carbamazepine, phenytoin)
• Lower folate concentrations
Tobacco and caffeinated coffee

Who should have their
Homocysteine level tested?


Sample Collection & Patient Preparation
Sample type: Blood (Serum/Plasma)
It can be measured at any time of day but preferably
overnight fasting and morning Sample. No special
preparations.
Once blood is drawn, Serum should separated within
1 hour.
serum or plasma is first treated with a reducing agent
that converts all Hcy species into the reduced form which
is measured either directly or after derivatization.
Homocysteine levels increase ~10% for every hour the
serum/plasma is not separated from the RBCs at room temperature.

How is the Homocysteine level measured ?
Currently, there are three main tHcy test methods
available to the clinical laboratories. They include:
• Chromatographic method (HPLC) :
• developed in the early 1980s, and is mainly used in
research laboratories.
• Immunoassay method:
• developed in the mid 1990s, and has been
automated for special immunoassay instruments.
• Enzyme cycling method:
• Latest, developed in last few years, Used on any
Automated clinical chemistry analyzer, and is quickly
becoming the preferred method for clinical
laboratories.07 March 2017 Dr. Furquan Alam 24

Advantages and Disadvantages of these
tHcy test methods:

http://www.who.int/mediacentre/factsheets/fs310/en/

Hyperhomocysteinemia and CVD
Cardiovascular Disease is the world’s
number one killing disease.
constituting about 30% of annual
worldwide deaths.
Up to 80% of all heart attacks occur in
people with normal cholesterol
In 25% of adults, the first sign of heart
disease is sudden death from a heart
attack.
Copyright 2010 - Drjoeesposito.com
July, 2006 Vol. 3 No. 4 Homocysteine - Revisited

The right idea but the wrong era
Dr Kilmer McCully, a researcher who graduated
from Harvard Medical School in the mid-1960s and
came up with the hypothesis that moderate
elevations of homocysteine could lead to heart
attacks and strokes.
It was the time that the cholesterol-heart-attack
theory was gaining tremendous momentum and Mc
Cully’s hypothesis clearly challenged its future.
He found himself moved down to the basement,
funding for his research dried up and he was
eventually asked to leave Harvard.

Prevalence of hyperhomocysteinemia is
not insignificant:
• General population: 5 - 10%
• Elderly population: 30 - 40%
• Pts with vascular disease: 20 - 40%.
Epidemiology
Annu Rev Med 1998;49:31-62. HCY and cardiovascular disease. Refsum H,
Ueland PM, et.al.
Jacques PF, Bostom AG, Wilson PW, et.al. Determinants of plasma total HCY
concentration in the Framingham Offspring cohort. Am J Clin Nutr. 2001;73:613-
621

Why is Homocysteine harmful?
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).
Copyright 2010 - Jeremy E. Kaslow, M.D. - all rights reserved

Homocysteine and disease
Bipolar Disorder
PCOS

Risk Factors for CVD
Non-modifiable
Advancing age
Heredity or family
history
Gender
Ethnicity or race
Major modifiable
High blood pressure.
Abnormal blood lipids
Tobacco use.
Physical inactivity
Obesity
Diabetes mellitus
Unhealthy diets
Novel Risk Factors
Excess homocysteine in
blood
Inflammation e.g. CRP
Abnormal blood coagulation:
e.g. Fibrinogen
Lp ( a)

What Homocysteine Does to Arteries
Homocysteine Lysyl residues of collagen
Interferes collagen crosslinking & bind to fibrillin 
endothelial dysfunction.
Homocysteine thiolactone (free radical)
Thiolates LDL particles
Aggregate
Endocytosed by macrophages
↑ed tendency for atherogenesis07 March 2017
Dr. Furquan Alam
33

What Homocysteine Does to Arteries
It changes coagulation factor levels so as to encourage
blood clot formation
It causes the smooth muscle cells that support the
arterial wall to multiply-part of the atherogenic process.
Homocysteine  activation of Hageman factor 
↑platelet adhesiveness  life threatening intravascular
thrombosis.
The net result is a threefold increase in heart attack risk
（Loscalzo et al., 1998;Maxwal., 2000 ）

If cholesterol and a high-fat diet are
the key culprits in heart disease,
why haven't we seen more of a
reduction in our number-one
disease killer over these past
several decades?

Homocysteine vs. Cholesterol
Researchers conclude that homocysteine
is up to 40 times more predictive than
cholesterol in assessing cardiovascular
disease risk.
Many studies concluded that the risk of
arteriosclerotic vascular disease does in
fact increase with the homocysteine level,
regardless of whether cholesterol is
normal or elevated.
heart44; 11-01-2004

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.

• tHcy levels are highly elevated in renal failure
patients.
• Impaired renal excretion and/or tubular
metabolism of Hcy, and extra renal factors, like
secondary vitamin deficiencies (e.g., in
connection with hemodialysis), genetic causes
and altered Hcy metabolism are among the
reasons.
Homocysteine & Renal Disease/Failure

Homocysteine & 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
N Engl J Med. 2004;350:2033-2041

Homocysteine & Pregnancy
Homocysteine conc. decreased in pregnancy due to
• Hemodilution
• Raised GFR
• Hormonal changes of pregnancy
• Increased fetal uptake

Homocysteine & Pregnancy Complication

Hyperhomocysteinemia, Pregnancy Complications and the Timing of Investigation
Re´gine P. Steegers-Theunissen,et al. VOL. 104, NO. 2, AUGUST 2004
The American College of Obstetricians and Gynecologists as accessed on 29th April 2012
NTDs
Other congenital
defects
spontaneous
miscarriage recurrent abortion
IUGR
Pre-eclampsia
placental abruption
Pre-term labour
Intrauterine fetal death
Hyperhomocysteinemia

Homocysteine & Pregnancy Complication
Values in Early Pregnancy are more reliable.
Folic acid supplements decrease homocysteine
levels during pregnancy and substantially
reduce the risk of central nervous system
malformations
2004 issue of "Clinical Chemistry

5,883 women in Norway were followed through
14,492 pregnancies with their outcomes and
complications recorded against their
homocysteine levels.
The Hordaland Homocysteine Study. JAMA 1995;274:1526–33

Higher homocysteine level and % Rise in
Risk of Complications
0
20
40
60
80
100
120
Pre -
eclampsia Premature
Birth Very Low
Birth Weight
32
38
101
07 March 2017 48

Homocysteine & PCOS
• In PCOS early atherosclerosis is not exclusively
dependent on hyperinsulinemia and elevated
lipid profile – PCOS patients are exposed to
significantly higher homocysteine levels which
might increase the cardiovascular disease risk.
Loverro G, Lorusso F, Mei L, Depalo R, Cormio G, Selvaggi L. The plasma homocysteine
levels are increased in polycystic ovary syndrome. Gynecologic and obstetric
investigation. 2002 Jun 6;53(3):157-62.

Homocysteine and 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.
New England Journal of Medicine", 2002;346(7):466-468.
:07 March 2017 Dr. Furquan Alam 50

Homocysteine and Alzheimer's Disease

CANCER – CUT YOUR RISK BY A THIRD
Cancer is triggered by damage to DNA – and having
a high homocysteine level means your DNA is more
vulnerable to damage
homocysteine levels have been found to be a very
good indicator of whether cancer therapies are
working. The homocysteine level rises when tumours
grow, and falls when they shrink.
Cancer Council Victoria 2011

REDUCE YOUR RISK OF DEATH FROM ALL
CAUSES
One of the best ways to extend your lifespan is by
reducing your homocysteine level. With every five-
point decrease in your H score, you will gain:
A 49% reduced risk of death from all causes.
A 50% reduced risk of death from cardiovascular
disease .
A 26% reduced risk of death from cancer .
A 104% reduced risk of death from causes other
than cancer or heart disease
2005 Orthomolecular conference

Homocysteine New studies
Raised Homocysteine levels are seen in sufferers
of chronic fatigue syndrome [CFS]
Homocysteine accelerates the aging process by
shortening telomeres.
RA patients are 20-30% more likely to have
higher Homocysteine levels than the normal
population
In traditionally-treated dialysis patients, 91% of
HD and 67% of PD patients have elevated Hcy
levels
Nutridisk 2011

Should Hyperhomocysteinemia Be Treated?
Arguments favoring treatment
Approximately 80 clinical and epidemiological studies
suggest that elevated homocysteine is a risk factor for
coronary heart , cerebro vascular, and peripheral
vascular diseases
Risk factor treatment of cardiovascular disease is an
accepted clinical practice
Treatment is inexpensive and unobtrusive under
medical supervision
Coronary Heart Disease ,Homocysteine,heart disease and stroke 2008

Should Hyperhomocysteinemia Be Treated?
Arguments against treatment
Many prospective studies shows that
Lowering homocysteine with folic acid
supplementation is safe, but does not reduce
the risk of vascular events
The American Heart Association has not yet
called hyperhomocysteinemia (high
homocysteine level in the blood) a major risk
factor for cardiovascular disease.
Coronary Heart Disease ,Homocysteine,heart disease and stroke 2008

Reduction in Homocysteine Levels
• Supplementation of B vitamins
• Folate, B6, and B12
• Restriction of methionine containing
substances
• Sesame seeds, brazil nuts, fish, meats
• Exercise

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.
Screening for vitamin B12 and folate deficiency in older persons. Am J
Clin Nutr 2003; 77: 1241-7.

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 in the late 1990’s 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

Treatment of hyperhomocysteinemia
Recheck every 6
months
64

Take Home Message
The lower the Hcy level, the lower the risk of
developing coronary artery disease and
suffering fatal heart attacks and strokes .
Your Homocysteine level is excellent 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 soon,
perhaps explosively.

Take Home Message
Hcy test is Costly but definitely not costlier than you
Life.
Tobacco, caffeine and excessive intake of
Methionine rich diet (Meat, Fish etc.) should be
avoided.

Prevention is always better than cure

Homocysteine: An Overlooked Biomarker in Clinical Medicine

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