Anemia and vitamins

Anemia & VitaminsVitamins & Cofactors
Total slides : 120 3March 10, 2014
Which vitamin deficiency do you think involved in
anemia?
Which vitamin deficiency do you think not involved
in anemia?

Outlines
 Anemia
 Introduction to vitamins and anemia
 Thiamin & anemia
 Riboflavin & anemia
 Niacin & anemia
 Pantothenic acid & anemia
 Pyridoxine & anemia
 Cobalamin & anemia
 Folic acid & anemia
 Vitamin A & anemia
 Vitamin K & anemia
 Vitamin E & anemia
 Vitamin C & anemia
 Biotin & anemia
 Orotic acid & anemia
 Other vitamins & anemia

Definition of Anemia
 A deficiency in the size or number of red blood cells or in the
amount of hemoglobin a red blood cell contains
 Decrease in blood hemoglobin below a person’s physiological
need
 Hemoglobin concentration below 95th percentile of healthy
reference population

Causes of Anemia
 Lack of required nutrients
 Loss of blood
 Chronic Disease
 Genetic Abnormalities
 Inadequate production of
red blood cells

Signs and symptoms of Anemia
Anemia occurs in many types, but the main symptom of most
anemias is fatigue. That's true for vitamin deficiency anemias,
which can also result in:
 Pale skin
 Sore mouth and tongue
 Shortness of breath
 Loss of appetite
 Diarrhea
 Numbness or tingling in your hands and feet
 Muscle weakness
 Mental confusion or forgetfulness
 Vitamin deficiencies usually develop slowly, over several months to years.
Vitamin deficiency symptoms may be subtle at first, but they increase as
the deficiency worsens

Classification of Anemia
Based on cell size (MCV)
 Macrocytic (large) MCV 100+ fl (femtoliters)
 Normocytic (normal) MCV 8-99 fl
 Microcytic (small) MCV<80 fl
Based on hemoglobin content (MCH)
 Hypochromic (pale color)
 Normochromic (normal color)

Types of Anemia
 Anemia due to B12 deficiency
 Anemia due to folate deficiency
 Anemia due to iron deficiency
 Hemolytic anemia
 Hemolytic anemia due to G-6-PD deficiency
 Idiopathic aplastic anemia
 Idiopathic autoimmune hemolytic anemia
 Immune hemolytic anemia
 Megaloblastic anemia
 Pernicious anemia
 Secondary aplastic anemia
 Sickle cell anemia

Introduction to vitamins and anemia
 Your body needs vitamins ( nutrients found in most foods) for
many reasons, including producing healthy red blood cells. If
your body is deficient in certain key vitamins, you can develop
a type of anemia ( a condition in which your blood is low on
healthy red blood cells ) called vitamin deficiency anemia.
 Red blood cells carry oxygen from your lungs to all parts of
your body. Without enough healthy red blood cells, your body
can't get the oxygen it needs to feel energized. To produce red
blood cells, your body needs iron and certain vitamins along
with adequate protein and calorie intake.
 Vitamin deficiency anemia can also lead to other health
problems. Fortunately, you can usually correct vitamin
deficiency anemia with supplements and dietary changes.

Thiamin & Anemia
Anemia & Vitamins

TRMA
 Thiamine-responsive megaloblastic anemia (TRMA) with
diabetes and deafness is an autosomal recessive disorder;
reported in less than 30 families.
 Megaloblastic anemia occurs between infancy and
adolescence. The anemia is corrected with pharmacologic
doses of thiamine (vitamin B1) (25-75 mg/day compared to
US RDA of 1.5 mg/day). However, the red cells remain
macrocytic. The anemia can recur when thiamine is
withdrawn. Progressive sensorineural hearing loss has
generally been early and can be detected in toddlers, is
irreversible, and may not be prevented by thiamine treatment.
The diabetes mellitus is non-type I in nature, with age of onset
from infancy to adolescence.

Diagnosis/testing
 The diagnosis of TRMA is based on an obligate triad of
clinical features described above. Examination of the bone
marrow reveals megaloblastic anemia with erythroblasts often
containing iron-filled mitochondria (ringed sideroblasts).
 SLC19A2, which encodes the high-affinity thiamine
transporter, is the only gene known to be associated with
TRMA. All individuals with the diagnostic phenotypic triad
evaluated by sequence analysis have identifiable mutations in
the SLC19A2 gene. Sequence analysis of SLC19A2 DNA is
available clinically.

Biochemical mechanism
 The underlying biochemical mechanisms responsible for these
conspicuous changes are, however, not very well defined and
remain somewhat speculative and controversial.
 There are basically 2 current theories, both rooted in the
concept that nucleotide synthesis is impaired as that in folate
and cobalamin (vitamin B12) deficiency.

 In one theory, lack of deoxythymidine triphosphate (dTTP)
retards the elongation of newly formed replicating segments of
DNA, resulting in fatally fractured pieces that trigger
premature apoptosis.
 In the other theory, build-up of deoxyuridine triphosphate
(dUTP) resulting from failure of conversion of dU to
thymidine causes an inordinate accumulation of dUTP, which
can then substitute for missing dTTP in the machinery of DNA
polymerase activity. Mis-incorporation of dUTP results in
excision of the faulty segment followed by misrepair while the
famine for dTTP persists, and thus ensues a futile cycle of
excision-misrepair. This, too, results in apoptosis, the final
common pathway of ineffective hematopoiesis in
megaloblastic anemia.

Role of thiamin in ribose 5-phosphate synthesis
 Through tracking the stable 13C-labeled glucose in fibroblasts
from patients with TRMA, Boros and colleagues concluded
that the underlying lesion in this condition resides in the
pentose cycle, specifically the transketolase enzyme, which
requires thiamine pyro-phosphate as a cofactor.
 Through a consideration of the several interconnected
pathways of glycolysis, the tricarboxylic acid cycle, and ribose
synthesis, the authors defined substrate flux in TRMA and
normal wild-type fibroblasts grown in both low- and high-
thiamine medium.

 They concluded that defective high-affinity thiamine transport
in TRMA leads to a critical reduction in de novo generation of
ribose with consequent cell-cycle arrest that triggers
precocious apoptosis. Their results clearly demonstrate a
selective and time-dependent loss of ribose synthesis in TRMA
patients that is most marked under thiamine-deprived culture
conditions and is partially restored by thiamine
supplementation, explaining the clinical responsiveness of
TRMA patients to high doses of thiamine.

Thiamin and pyruvate dehydrogenase complex

Role of the TCA cycle in anabolism

Diagnosis
 To establish the extent of disease in an individual diagnosed
with thiamine-responsive megaloblastic anemia syndrome
(TRMA), the following evaluations are recommended:
 Peripheral blood count and bone marrow analysis for evidence of megaloblastic
anemia
 Serum folate concentration, serum vitamin B12 concentration, and serum iron
studies to exclude other entities
 Fasting serum glucose concentration, oral glucose tolerance test (OGTT), and
urine analysis to diagnose diabetes mellitus
 Hearing test
 Ophthalmologic evaluation
 Cardiac evaluation, including echocardiography

Treatment
 Early administration of pharmacologic doses of oral thiamine
(25-75 mg/day compared to US RDA of 1.5 mg/day)
ameliorates the megaloblastic anemia and the diabetes
mellitus. It may prevent further deterioration of hearing
function.
 Whether treatment with thiamine from birth, or even
prenatally, could reduce the hearing defect is a matter of
conjecture.

Riboflavin & Anemia
Anemia & Vitamins

 Riboflavin deficiency has been associated with the
development of normochromic ,normocytic anaemia .
 It may be one of the most common vitamin deficiencies among
the people of developing nations.
 This anemia is associated with reticulocytopenia;
leukocytes and platelets are generally normal.
 Administration of riboflavin to deficient patients causes
reticulocytosis, and the concentration of haemoglobin
returns to normal.

 Effects on iron absorption:
 A FMN-dependent oxidoreductase (NADPH-ferrihemoprotein
reductase) catalyses the removal of iron from storage ferritin (by
reducing heme-thiolate-dependent monooxygenases).
 Riboflavin affects iron absorption by maintaining the absorptive
capacity of gastrointestinal villi .
 Effects on heme metabolism
 Protoporphyrinogen oxidase at the iner mitochondrial membrain
contains one FAD moiety per homodimer ,oxidizes
protoporphyrinogen-IX to protoporphyrin-IX.
 NADPH dehydrogenase (EC1.6.99.1) reduces biliverdin to bilirubin in
the liver and also may protect against oxidative damage.

Effects on other vitamins metabolism that their
deficiencies are related to anemia:
 Metabolism of vitamin B12
 Cobalamin reductase
 Aquacobalamin reductase/NADPH
 Aquacobalamin reductase/NADH
 Metabolism of vitamin B6:
 Pyridoxamine-phosphate oxidase interconverts the B6 vitamins
pyridoxamine,pyridoxine and pyridoxal, as well as their phosphates.
 Metabolism of folic acid:
 The FAD-dependent methylen tetrahydrofolate reductase is needed for
folate metabolite recycling(with a reduction of its activity higher folate
intakes are needed to avoid deficiency).

 Metabolism of vitamin B2:
 Maintains supplies of vitamin B3 with the help of an enzyme
kynurenine mono-oxygenase and vitamin B2 in its FAD form.
 Metabolism of vitamin C:
 Thioredoxin reductase regenerates reduced glutathione, which is used
for dehydroascorbate reductase.
 Metabolism of vitamin K:
 NADPH dehydrogenase (EC1.6.99.6) and two forms of NAD(P)H
dehydrogenase (EC1.6.99.2) reactive vitamin K (dicomarol inhibitable)
and also provide important antioxidant protection.
 Metabolism of vitamin A:
 Retinal dehydrogenase is the enzyme that generates retinoic acid from
retinal.

Niacin & Anemia
Anemia & Vitamins

 Niacine deficiency has produced macrocytic anaemia among
human patients with pellagra although this is usually due to an
accompanying deficiency in folic acid.
 Niacin nutritional deficiency causes hemorrhagic diarrhea,
dermatitis, anemia and a severe stomatitis with ulceration of
the mouth and tongue ('black tongue').

Role of niacin in citric acid cycle
NAD+ NADH + H+
Isocitrate Alpha-ketogluterate
NAD+ NADH + H+
Alpha-ketogluterate Succinyl CoA
NAD+ NADH + H+
Malate Oxaloacetate

Pantothenate & Anemia
Anemia & Vitamins

 Rats fed a purified diet low in pantothenic acid developed
granulocytopenia and anemia singly or in combination. In the
former, the marrow showed marked depletion of granulocytes,
particularly of the more mature cells, and a slight increase in
erythroid cells. In combined granulocytopenia and anemia the
granulocytes of the marrow were still further reduced and the
erythroid cells were also depleted. Marked reduction in the
number of megakaryocytes occurred both in the
granulocytopenic and in the granulocytopenic and anemic rats.
 Following treatment with combined folic acid, pantothenic
acid, and niacinamide, granulocytopenic rats responded by
showing a prompt rise in lymphocyte and polymorphonuclear
leukocyte count, marked granulocyte response of the bone
marrow

 Pantothenic acid as a part of coenzyme A is essential for Heme
formation in hemoglobin.
 The production of acetyl-C0A from pyruvate and succinyl-
CoA from alpha-ketoglutarate constantly consumes large
amounts of CoA.
 Succinyl-CoA is needed for D-ALA synthesis the first step in
heme production.

Pyridoxine & Anemia
Anemia & Vitamins

 Vitamin B6 (pyridoxine) deficiency can disturb heme synthesis
and lead to normocytic, microcytic or sideroblastic anemia.
Treatment of sideroblastic anemia with vitamin B6 has resulted
in the restored activity of erythroblastic -aminolevulinic acid
synthetase (ALAS), the rate-limiting enzyme in heme
synthesis, followed by correction of the hematological
abnormalities.
 Heme biosynethsis begins in the mitochondrion with the
formation of 5-aminolevulinic acid. This molecule moves to
the cytosol where a number of additional enzymatic
transformations produce coproporphyrinogin III. The latter
enters the mitochondrion where a final enzymatic conversion
produces protophorphyrin IX. Ferrochelase inserts iron into
the protophorin IX ring to produce heme.

 In Germany, after treating children hospitalized with iron
deficiency anemia for 8 days with iron plus vitamin B6, there
was an apparent acceleration of heme synthesis, reflected in
Hb concentrations that were higher than observed in children
who received only iron

 Vitamin B6 may also inhibit sickling of
erythrocytes in sickle-cell anemia
(SCA), possibly increasing erythrocyte
counts, Hb concentrations and Hct
among SCA patients
 Vitamin B6 deficiency is rare, but
treatment with B6 may be effective in
correcting the hematological
abnormalities of sideroblastic anemia.

 The bone marrow aspirate from a patient with sideroblastic anemia in this
photomicrograph was stained with Perl's Prussian blue. The arrow indicates a
normoblast with a greenish halo of material stained by Perl's Prussian blue
surrounding the nucleus. Electron microscopic examination would should these to
be iron-laden mitochondria.

Effect of Vitamin B6 on niacin synthesis
Kynureninase (PLP)
Xanthurenic
Acid
TRYPTOPHAN
N-FORMYLKYNURENINE
KYNURENINE
3-OH-KYNURENINE
3-OH ANTHRANILIC ACID
QUINOLINIC ACID
NIACIN
acetyl
CoA
acetoacetyl
CoA

Cobalamin & Anemia
Anemia & Vitamins

B12 deficiency Anemia
This picture shows large, dense,
oversized, red blood cells
(RBCs) that are seen in
Megaloblastic anemia can
occur when there is a
deficiency of vitamin B-12.
Megaloblastic anemia - view of red blood cells

CAUSES OF MACROCYTOSIS
ETOH
DRUGS
HEMOL
LIVER
MDS
OTHER
B12/
FOLATE
Vitamins & Cofactors Anemia & Vitamins
Total slides : 47March 10, 2014

Age of onset
0
5
10
15
20
25
30
35
'10-20 20-30 30-40 40-50 50-60 60-70 70-80 80-90 90-100

 Pernicious anemia
 Rare autoimmune disease
 Failure to absorb B12 from food
 Very common in older patients
 Drugs
 Metformin
 PPI
 Dramatic reduction in B12 absorption
Causes

Physiologic roles of vitamin B12
 Conversion of propionyl-CoA to methylmalonyl CoA and
finally to succinyl-CoA
 Transfer of a methyl group from methyl-tetrahydrofolate
(methyl-THF) via Cbl to homocysteine to form methionine —
This reaction has two important effects: it reduces the plasma
concentration of homocysteine which is probably toxic to
endothelial cells; and, perhaps more importantly, it
demethylates THF
 Demethylation is a critical step in DNA synthesis

Intense erythroid hyperplasia in the marrow but
relative reticulocytopenia

Symptoms
 Loss of appetite
 Diarrhea
 Numbness and tingling of hands and feet
 Paleness
 Shortness of breath
 Fatigue
 Weakness
 Confusion or change in mental status in severe or advanced cases

Exams and Tests
A physical exam may show problems with reflexes or positive Babinski
reflex.
The following tests will be done:
 CBC
 Bone marrow examination
 LDH
 Vitamin B12 level
 Schilling test
 Antibody test
 Methylmalonic acid test

Bone marrow aspiration
 A small amount of bone marrow is
removed during a bone marrow
aspiration. The procedure is
uncomfortable, but can be tolerated
by both children and adults. The
marrow can be studied to determine
the cause of anemia, the presence
of leukemia or other malignancy, or
the presence of some "storage
diseases" in which abnormal
metabolic products are stored in
certain bone marrow cells.

Schilling test
 The Schilling test is performed to
evaluate vitamin B12 absorption.
B12 helps in the formation of red
blood cells, the maintenance of the
central nervous system, and is
important for metabolism.
Normally, ingested vitamin B12
combines with intrinsic factor,
which is produced by cells in the
stomach. Intrinsic factor is
necessary for vitamin B12 to be
absorbed in the small intestine.
Certain diseases, such as
pernicious anemia, can result when
absorption of vitamin B12 is
inadequate.

LDH
Alternative Names
 Lactate dehydrogenase; Lactic acid dehydrogenase
Definition
LDH is a blood test that measures the amount of lactate dehydrogenase (LDH).
How the Test is Performed
 The health care provider draws blood from a vein or from a heel, finger,
toe, or earlobe. The laboratory quickly spins (centrifuges) the blood to
separate the serum (liquid portion) from the cells. The LDH test is done on
the serum.

Antibodies test
 Your doctor may draw a sample of your blood to check for
antibodies to intrinsic factor. In the majority of cases, vitamin
B-12 deficiency is due to a lack of intrinsic factor — a protein
secreted by the stomach necessary for the absorption of
vitamin B-12. The presence of antibodies to intrinsic factor
indicates pernicious anemia.

Methylmalonic acid test
 You may undergo a blood and urine test to measure the
presence of a substance called methylmalonic acid. The level
of this substance is higher in people with vitamin B-12
deficiency.

Treatment
 Treatment depends on the specific cause of B12 deficiency
anemia.
 Pernicious anemia requires lifelong vitamin B12 injections.
Those with anemia due to a lack of vitamin B12 may be told to
take vitamin supplements and to follow a more balanced diet.
It may be treated initially with vitamin B12 injections.
 Anemia caused by malabsorption is treated with vitamin B12
injections until the condition improve
 Outlook (Prognosis)
 Treatment for this form of anemia is usually effective

Prevention
Anemia caused by a lack of vitamin B12 can be prevented by
following a well-balanced diet. B12 injections can prevent
anemia after surgeries known to cause vitamin B12 deficiency.
Early diagnosis and prompt treatment can limit the severity
and complications of this anemia.

Folic Acid & Anemia
Anemia & Vitamins

Folate-deficiency anemia
 Folate-deficiency anemia is a decrease in red blood cells
(anemia) caused by folate deficiency.
 The hematologic manifestations of folate deficiency are
similar to those of Cbl deficiency but neurologic abnormalities
do not occur
Symptoms
 Tiredness
 Headache
 Pallor

Causes
 Nutritional deficiency Substance abuse ,Alcoholism Poor
dietary intake ,Overcooked foods ,Depressed patients, Nursing
homes
 Malabsorption Sprue, Inflammatory bowel disease Infiltrative
bowel disease,Short bowel syndrome
 Drugs (various mechanisms) Methotrexate, Trimethoprim,
Ethanol, Phenytoin
 Increased requirements Pregnancy, lactation, Chronic
hemolysis, Exfoliative dermatitis

Folate metabolism
METHYL THF
THF
THF PG
DHF PG
5,10
METHYLENE
THF PG
dUMP
dTMP
DNA
HOMOCYSTEINE
METHIONINE
METHIONINE
SYNTHASE

Exams and Tests
 Low red blood cell folate level.
 A complete blood count (CBC) shows anemia and large red
blood cells.
 A bone marrow examination is rarely necessary, but shows
megaloblasts.

Treatment
 The goal is to treat the cause of the anemia, which may be poor diet or a
malabsorption disease.
 Oral or intravenous folic acid supplements may be taken on a short-term
basis until the anemia has been corrected, or -- in the case of poor
absorption by the intestine -- replacement therapy may be lifelong.
 Dietary treatment consists of increasing the intake of green, leafy
vegetables and citrus fruits.
Outlook (Prognosis)
 Anemia usually responds well to treatment within 2 months.

Possible Complications
 Symptoms of anemia can cause discomfort. In a pregnant
woman, folate deficiency has been associated with neural tube
or spinal defects (such as spina bifida) in the infant.

Vitamin A & Anemia
Anemia & Vitamins

Vitamin A & anemia
 In many developing countries vitamin A deficiency (VAD)
is considered to be a major public health problem and
concurrently the prevalence of anemia is high in
populations affected by VAD.
 190-255 millions preschool-aged children throughout the
world are vitamin A deficient, with some 3–5 million having
xerophthalmia, and 500 000 becoming blind and dying each
year. Vitamin A deficiency may be responsible for 25–35% of
all early childhood deaths in high risk regions of the
developing world, attributed to increased severity of infection
in a deficient state.

Animal studies
Vitamin A-deficient rats indicate:
 Losses of hematopoietic tissue in bone marrow.
 Splenic accumulation of hemosiderin.
Adding of vitamin A to the rats diet:
 Regeneration of the bone marrow.
 Disappearance of hemosiderin from the spleen.
 Enhanced erythroblastic activity.

Human studies
In human studies:
 Positive correlation between serum retinol concentration and
Hb level.
 The findings suggest that adequate vitamin A status can help
maintain adequacy of plasma iron to supply body tissues.
 Intake of fortified food items with vitamin A has been resulted
in elevation serum iron levels,transferrin saturation and serum
ferritin levels.
 Result: increasing iron availability to tissues.

 Vitamin A appears to be involved in the pathogenesis of
anemia through diverse biological mechanisms, such as:
 The enhancement of growth and differentiation of erythrocyte
progenitor cells
 Potentiation of immunity to infection
 Reduction of the anemia of infection
 Mmobilization of iron stores from tissues.
 Epidemiological surveys show that the prevalence of anemia is
high in populations affected by vitamin A deficiency in
developing countries. Improvement of vitamin A status has
generally been shown to reduce anemia.

A combination of vitamin A with iron and zinc is more effective
than with iron alone.
 This could reflect Zn association with increases in plasma
vitamin A and retinol-binding protein.
 The effect of vitamin A on risk of anemia appears to be more
variable in pregnancy than childhood.
 Haemoconcentration associated with low vitamin A status can
mask anemia.

 It has been reported that supplementation with vitamin A
increases hemoglobin levels and packed cell volumes in
humans with low vitamin A status, thereby contributing to
the control of nutritional anemia; furthermore, a
synergistic interaction exists between vitamin A and iron
in combined therapy (Suharno et al., 1993). Some
important effects of vitamin A are to support
erythropoiesis in the bone marrow and to mobilise iron
from body stores (Bloem, 1995; Roodenburg et al., 1996;
Semba and Bloem, 2002). However, in rats and chickens
vitamin A deficiency (VAD) is accompained by
imbalances in water regulation, in particular a decrease
in extracellular water, which may lead to
hemoconcentration as the VAD proceeds (Sure et al.,
1929; McLaren et al., 1965; Nockels and Kienholz, 1967;
Corey and Hayes, 1972; Mejı´a et al., 1979a;
Roodenburg et al., 1994, 1996).

Possibly mechanism of vitamin A deficiency anemia
Vitamin A deficiency may induce anemia by:
 Impairing the differentiation and proliferations of pluripotent
haematopoietic cells.
 Disturbing renal and hepatic erythropoietin synthesis.
 Disturbing GI absorption.
 Reducing mobilization of body iron stores..

Vitamin K & Anemia
Anemia & Vitamins

Vitamin K and hemolytic anemia
 Vitamin K is necessary for synthesis in the liver of factor II
(prothrombin), factor VII (proconvertin), factor IX
(thromboplastin), and factor X. Deficiency of vitamin K or
disturbances of liver function may lead to deficiencies of these
factors. When the prothrombin level falls to about 10 to 15%
of normal, even slight trauma may cause bleeding; when the
level is below 10%, spontaneous hemorrhage may occur, in
the form of hematoma, hematemesis, hematuria or melena.
The mechanism by which vitamin K promotes formation in the
liver of clotting factors II, VII, IX, and X is not known.

 Newborns should be observed for vitamin K deficiency. The
incidence of vitamin K deficiency is higher in breast-fed
infants.
 In newborns, particularly premature infants,
hyperbilirubinemia and hemolytic anemia have been reported.
The risk is much less with phytonadione than other vitamin K
preparations unless high doses (10 to 20 mg) are given.
 In infants (particularly premature babies), excessive doses of
vitamin K analogs during the first few days of life may cause
hyperbilirubinemia; this in turn may result in severe hemolytic
anemia, hemoglobinuria, kernicterus, leading to brain damage
or even death.

Hemorrhagic Disease of the Newborn: Prophylaxis:
 In its 1997 clinical practice guidelines on vitamin K
administration, the Canadian Paediatric Society recommends
that vitamin K1 be given as a single i.m. injection to all
newborns within 6 hours of birth, at a dose of 1 mg for infants
with a birthweight of >1 500 g and 0.5 mg if birthweight is £1
500 g.

Vitamin K deficiency
 Vitamin K deficiency may occur in patients with biliary
obstruction or other conditions limiting absorption of vitamin
K such as celiac disease, ulcerative colitis, sprue, regional
enteritis, cystic fibrosis, intestinal resection, and in patients
receiving drugs that may affect liver function or intestinal
flora.

Vitamin E & Anemia
Anemia & Vitamins

Vitamin E & hemolytic anemia
 Hemolytic anemia results from the deficiency of the enzyme
glucose-6-phosphate dehydrogenase or of glutathione
synthetase. Red blood cells become more sensitive to attack by
free radicals, because they cannot form lipids in which
vitamins can be stored. Increasing the blood level of vitamin E
has been found to be useful in this disease.
Function :
as an antioxidant, scavenging highly reactive free radicals and
protecting the PUFAs of cellular membranes from oxidative
destruction.

Vitamin E and membrane lipid oxidation As part of the antioxidant network, a-tocopherol (a-OH) forms a
tocopheroxyl radical (a-TO·) when it intercepts a peroxyl radical (ROO·) in a cell membrane. In the
absence of vitamin E, these ROO· can abstract a hydrogen from PUFA (RH) and generate both a
hydroperoxide (ROOH) and another carbon-centered radical (R·), which in the presence of oxygen (O2)
will form a ROO· and thus a lipid peroxidation chain reac-tion occurs. If a-tocopherol (a-TOH) is present it
intercepts the radical 1000 times faster than the radical reacts with PUFA, and both a ROOH and an a-TO·
are formed. This a-TO· radical can be detoxified and a-TOH regenerated by intracellular antioxidants
including vitamin C, glutathione, and reducing equivalents (NAD(P)H) derived from oxidative metabolism.

Animal studies
Animal studies have observed:
 The development of severe anemia in primates.
 Morphological abnormalities of the bone marrow among
primates.
Treatment with vitamin E improved blood parameters
among these animals.

Human studies
 Pre term and LBW infants are born with low serum and tissue
concentration of vit E.
 Vit E deficiency induced anemia in infants has been
characterized by red blood hemolysis and oedema that resolves
promptly following vit E treatment.
 Vit E is routinly given to preterm infants in developed country
to protect against the potential oxidative caused by iron
supplementation
 Increasing tocopherol to PUFA ratio to lower oxidant agents
such as iron in infant formula.

Vitamin E & fanconi anemia
 a-Tocopherol (AT) decreased the frequency of chromosomal
damage (under basal and inhibited G2 repair conditions) and
the duration of G2 in FA cells. This antioxidant protective
effect, expressed as the decrease in chromatid breaks, was
greater in FA cells (50.8%) than in controls (25%).

Effects of vitamin E on heme synthesis
 Vitamin E has a stimulatory effect on heme synthesis,
apparently through its action on ALAD and on 5-
aminolevulinic acid synthetase (ALAS).
 Addition of vitamin E to the diets of lead-intoxicated rabbits
coused a diminution in the anemia and coproporphyrinuria,
which had resulted from plumbism.(Nair et al. , deRosa)

Vitamin E deficiency
 Vitamin E deficiency can result from a low intake of fresh fruit
and vegetables and other foods rich in vitamin E Deficiency
can also occur in those individuals who cannot absorb fat. In
addition, damage to the pancreas, bile duct, liver, and surgical
removal of the major portion of the digestive tract can cause
vitamin E deficiency. The plasma level of vitamin E in normal
adults is about 10 mcg/ml; a plasma level of 5 mcg/ml or less
is considered and indication of vitamin E deficiency.

Vitamin C & Anemia
Anemia & Vitamins

Vitamin C effects on anaemia
 Vitamin C defciency has been associated with various
forms of anemia, but it is still unclear whether vitamin C
(ascorbate) is directly involved in hematopoiesis or if
anemia arises indirectly through the interactions of
vitamin C with folate and iron metabolism. In its role as a
reducing agent, vitamin C can facilitate iron absorption
from the gastrointestinal tract and enable its mobilization
from storage.
 Iron and ascorbate form an iron chelate complex that is
more soluble in the alkaline environment of the small
intestine and, as a result, more easily taken up.

 Vitamin C may counteract the inhibition of iron absorption by
dietary phytates and tannins.
 Ascorbic acid also activates the enzyme folic acid reductase to
form THF ,the active form of folate which prevent
 Vitamin C possibly prevent hemolysis resulting from
compromised celluar antioxidant defence mechanism.

Vitamin C mechanism
Ultimately Vitamin C may:
 improve absorption of non-heme iron
 protect against oxidative damage
 counteract the effects of iron absorption inhibitors.
 increase serum iron , ferritin and Hb concentrations among
children and non-pregnant subjects.

Vitamin C deficiency
 Vitamin C deficiency is evident when serum ascorbate
falls below 11.4 mmol /1. Groups that have been
identifed as being at risk of vitamin C deficiency include
pregnant and lactating women, infants fed exclusively
cow's milk, elderly men and smokers.

Biotin & Anemia
Anemia & Vitamins

 Biotin is one of the least-studied vitamins, particularly in
relation to mitochondrial function and the extent of its
nutritional deficiency in humans.
 The most important function of Biotin is to ensure proper
growth. Not only does it help produce DNA fatty acids and
other essential nucleic acids, it also helps the cells grow and
replicate. It also plays a vital role in the production of bone
marrow and thus the tissues of the central nervous system and
muscles benefit from this vitamin. Vitamin H is also known to
be involved in the process that helps transfer carbon dioxide.

Effects of biotin on heme synthesis
 Biotin is a coenzyme in 5 different biotin-dependent
carboxylases (BDC), which catalyze carboxylation reactions :
pyruvate carboxylase (PC), propionyl-CoA carboxylase
(PCC), 3-methylcrotonyl-CoA carboxylase (MCC), acetyl-
CoA carboxylase (ACC)-2, and ACC-1. The first 4 are located
in the mitochondria. PC, PCC, and MCC catalyze anaplerotic
reactions and replenish tricarboxylic acid (TCA) cycle
intermediates .

Effects of biotin on heme synthesis
 BD has a detrimental effect on the level of TCA cycle
intermediates. A deficiency in PC directly decreases
production of oxaloacetate. A deficiency in PCC decreases
production of succinyl-CoA and causes propionyl-CoA to
accumulate, which interacts via a side reaction with
oxaloacetate to form methylcitrate. Additionally, low activity
of MCC causes methylcrotonyl-CoA to accumulate in the
mitochondria where it reacts with glycine and potentially
depletes this amino acid from the mitochondrial matrix.
 Succinyl-CoA from the TCA cycle and glycine are the
precursors for heme biosynthesis. Heme synthesis starts in the
mitochondria by condensing succinyl-CoA with glycine to
form -aminolevulinate, the first metabolite committed to heme
synthesis

Results
 Heme level and synthesis were markedly decreased in BD cells , indicating
that adequate heme synthesis requires biotin and that BD can cause heme
deficiency. Thus, biotin should be considered the 8th member of the group
of vitamins and minerals required for adequate heme synthesis . The
decrease in iron uptake in BD cells is unexpected, because heme deficiency
should be expected to cause a compensatory increase in iron uptake . A
possible explanation for the lack of an increase in iron uptake in BD cells is
that the heme deficiency caused by BD is due to a decrease in succinyl-
CoA, which lowers the production of porphyrins. Porphyrins are
intermediates in the biosynthesis of heme. These results suggest that
optimal uptake of iron requires that the mechanisms for iron assimilation
into heme remain intact. Adequate levels of biotin appear to be essential for
adequate iron uptake. Thus, for correcting iron deficiency in humans, it
may be important to ensure biotin adequacy.

Orotic acid & Anemia
Anemia & Vitamins

 Orotic acid plays a central role in the metabolism of folic acid
and vitamin B-12, and may enhance the transportation of
minerals across cell membranes.
 Orotic acid and folate are also involved in DNA synthesis.
Many of the vitamin-like effects of orotic acid are undoubtedly
due to its role in RNA and DNA synthesis. Our bodies produce
OA as an intermediate in the manufacture of the pyrimidine
bases uracil, cytosine, and thymine. Together, these
pyrimidines constitute half of the bases needed for RNA/DNA,
the other half coming from the purine bases adenine and
guanine which are synthesized independently of orotic acid.

Mechanism of OA action
 The oral administration of the pyrimidine precursor orotic acid
in doses of 3 to 6 Gm. daily to patients with pernicious anemia
in relapse produced with some regularity Partial remissions in
the manifestations of vitamin B12 deficiency.
 The early effects of orotic acid in pernicious anemia resembled
those of small amounts of B12. Reticulocytosis appeared 7 to
14 days after the start of therapy.

 B12 is concerned with pyrimidine biosynthesis.
 The degree of remission that can be produced in patients with
pernicious anemia in relapse by the administration of orotic
acid suggests, that one major consequence of vitamin B12
deficiency in the human is a defect in pyrimidine biosynthesis
and/or incorporation. Other processes, such as purine ring
formation, may also be affected. The mechanism by which
orotic acid induces partial remissions in pernicious anemia is
unknown.

 It could serve merely as a metabolite which when supplied
from exogenous sources would circumvent a block in its
synthesis or in that of a precursor. Increasing the supply of
orotic acid could possibly overcome by mass action a defect in
the synthetic pathway at a later stage. In view of demonstrated
feed-back regulatory mechanisms in pyrimidine synthesis,

Other vitamins & Anemia
Anemia & Vitamins

Para-aminobenzoic acid, as part of the coenzyme tetrahydrofolic
acid, aids in the metabolism and utilization of amino acids and
is also supportive of blood cells, particularly the red blood
cells. PABA supports folic acid production by the intestinal
bacteria.
PABA

Inositol
 Usually considered part of the vitamin B complex. It is thought that along
with choline, inositol is necessary for the formation of lecithin within the
body. Involved in calcium mobilization.
 IP6 regulates the oxygen capacity of red blood cells; it reduces both
cholesterol and trigylcerides, as well as preventing heart damage during a
heart attack.
 Research has shown that IP6 can help prevent sikle cell anemia
 Anemia has been reported as a clinical sign of inositol deficiency in
salmonids (Halver, 1982). Waagbø et al. (1998) observed a positive
correlation between blood hemoglobin concentrations and dietary levels of
inositol in Atlantic salmon.

adenine
 Acts as a co-enzyme with other vitamins to enhance
metabolism.
 Acts as a precursor for assimilation of other B-vitamins.
 Strengthens the immune system response.
 Promotes cell formation and normal growth.
 Prevents cellular mutation and free radical formation.
 Helps to balance blood sugar levels.
 Deficiency of adenine associated whit blood and skin disorders

Vitamin D

 The association of hypercalcemia and anemia suggested a
neoplastic origin; this idea was rejected when results of
additional examinations became available. High vitamin D
levels could directly affect hematopoietic cells or act through
high calcium levels, which inhibit erythroid colony formation
in vitro and erythropoietin production in vitro and in vivo. That
calcium is more important than vitamin D itself is supported by
the course of our patient, whose anemia subsided after
normalization of calcium levels, despite high vitamin D levels.
 In addition to the danger of extemporaneous formulations,
which carry a higher risk for error than factory-made pills,
anemia is another potential complication of vitamin D
intoxication.

Laetrile
 Relationship between laetrile and anemia…
 What is your idea?

Anemia and vitamins

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