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.
Z Score,T Score, Percential Rank and Box Plot Graph
Anemia & vitamins
1. Isfahan University of Medical Science, School of
Vitamins & Cofactors Anemia & Vitamins
Pharmacy
Department of Clinical Biochemistry
June 26, 2012 Total slides : 120 1
3. Vitamins & Cofactors Anemia & Vitamins
Which vitamin deficiency do you think
involved in anemia?
Which vitamin deficiency do you think
not involved in anemia?
June 26, 2012 Total slides : 120 3
4. Vitamins & Cofactors Anemia & Vitamins
O u t lin e s
A n e m ia
In t r o d u c t io n t o v it a m in s a n d a n e m ia
T h ia m in & a n e m ia
R ib o f la v in & a n e m ia
N ia c in & a n e m ia
P a n t o t h e n ic a c id & a n e m ia
P y r id o x in e & a n e m ia
C o b a la m in & a n e m ia
F o lic a c id & a n e m ia
V it a m in A & a n e m ia
V it a m in K & a n e m ia
V it a m in E & a n e m ia
V it a m in C & a n e m ia
B io t in & a n e m ia
O r o t ic a c id & a n e m ia
O t h e r v it a m in s & a n e m ia
June 26, 2012 Total slides : 120 4
6. Vitamins & Cofactors Anemia & Vitamins
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
June 26, 2012 Total slides : 120 6
7. Vitamins & Cofactors Anemia & Vitamins
Causes of Anemia
Lack of required nutrients
Loss of blood
Chronic Disease
Genetic Abnormalities
Inadequate production of
red blood cells
June 26, 2012 Total slides : 120 7
8. Vitamins & Cofactors Anemia & Vitamins
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
June 26, 2012 Total slides : 120 8
9. Vitamins & Cofactors Anemia & Vitamins
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)
June 26, 2012 Total slides : 120 9
10. Vitamins & Cofactors Anemia & Vitamins
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
June 26, 2012 Total slides : 120 10
11. Vitamins & Cofactors Anemia & Vitamins
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.
June 26, 2012 Total slides : 120 11
13. Vitamins & Cofactors 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.
June 26, 2012 Total slides : 120 13
14. Vitamins & Cofactors Anemia & Vitamins
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.
June 26, 2012 Total slides : 120 14
17. Vitamins & Cofactors Anemia & Vitamins
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.
June 26, 2012 Total slides : 120 17
18. Vitamins & Cofactors Anemia & Vitamins
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.
June 26, 2012 Total slides : 120 18
19. Vitamins & Cofactors Anemia & Vitamins
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.
June 26, 2012 Total slides : 120 19
20. Vitamins & Cofactors Anemia & Vitamins
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.
June 26, 2012 Total slides : 120 20
21. Vitamins & Cofactors Anemia & Vitamins
Thiamin and pyruvate dehydrogenase complex
June 26, 2012 Total slides : 120 21
22. Vitamins & Cofactors Anemia & Vitamins
Role of the TCA cycle in anabolism
June 26, 2012 Total slides : 120 22
23. Vitamins & Cofactors Anemia & Vitamins
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
June 26, 2012 Total slides : 120 23
24. Vitamins & Cofactors Anemia & Vitamins
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.
June 26, 2012 Total slides : 120 24
26. Vitamins & Cofactors 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
June 26, 2012 Total slides : 120 26
27. Vitamins & Cofactors Anemia & Vitamins
Biochemical mechanism
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.
June 26, 2012 Total slides : 120 27
28. Vitamins & Cofactors Anemia & Vitamins
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).
June 26, 2012 Total slides : 120 28
29. Vitamins & Cofactors Anemia & Vitamins
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.
June 26, 2012 Total slides : 120 29
31. Vitamins & Cofactors 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').
June 26, 2012 Total slides : 120 31
36. Vitamins & Cofactors 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
June 26, 2012 Total slides : 120 36
37. Vitamins & Cofactors Anemia & Vitamins
Biochemical mechanism
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.
June 26, 2012 Total slides : 120 37
39. Vitamins & Cofactors 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 δ-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.
June 26, 2012 Total slides : 120 39
41. Vitamins & Cofactors Anemia & Vitamins
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
June 26, 2012 Total slides : 120 41
42. Vitamins & Cofactors Anemia & Vitamins
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.
June 26, 2012 Total slides : 120 42
43. Vitamins & Cofactors Anemia & Vitamins
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.
June 26, 2012 Total slides : 120 43
44. Vitamins & Cofactors Anemia & Vitamins
Effect of Vitamin B6 on niacin synthesis
TRYPTOPHAN
N-FORMYLKYNURENINE
KYNURENINE
Xanthurenic 3-OH-KYNURENINE
Acid Kynureninase (PLP) acetyl
CoA
3-OH ANTHRANILIC ACID
acetoacetyl
QUINOLINIC ACID CoA
NIACIN
June 26, 2012 Total slides : 120 44
46. Vitamins & Cofactors Anemia & Vitamins
B12 deficiency Anemia
This picture shows large, dense,
oversized, red blood cells
(RBCs) that are seen in
megaloblastic anemia.
Megaloblastic anemia can
occur when there is a
deficiency of vitamin B-12.
Megaloblastic anemia - view of red blood cells
June 26, 2012 Total slides : 120 46
47. Vitamins & Cofactors Anemia & Vitamins
CAUSES OF MACROCYTOSIS
OTHER
MDS
LIVER ETOH
HEMOL
DRUGS
B12/
FOLATE
June 26, 2012 Total slides :
Total slides : 120 47
48. Vitamins & Cofactors Anemia & Vitamins
Age of onset
35
30
25
20
15
10
5
0
'10-20 20-30 30-40 40-50 50-60 60-70 70-80 80-90 90-100
June 26, 2012 Total slides : 120 48
49. Vitamins & Cofactors Anemia & Vitamins
Causes
Pernicious anemia
Rare autoimmune disease
Failure to absorb B12 from food
Very common in older patients
Drugs
Metformin
PPI
Dramatic reduction in B12 absorption
June 26, 2012 Total slides : 120 49
50. Vitamins & Cofactors Anemia & Vitamins
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
June 26, 2012 Total slides : 120 50
52. Vitamins & Cofactors Anemia & Vitamins
Intense erythroid hyperplasia in the marrow but
relative reticulocytopenia
June 26, 2012 Total slides : 120 52
53. Vitamins & Cofactors Anemia & Vitamins
Symptoms
Loss of appetite
Diarrhea
Numbness and tingling of hands and feet
Paleness
Shortness of breath
Fatigue
Weakness
Sore mouth and tongue
Confusion or change in mental status in severe or advanced cases
June 26, 2012 Total slides : 120 53
54. Vitamins & Cofactors Anemia & Vitamins
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
June 26, 2012 Total slides : 120 54
55. Vitamins & Cofactors Anemia & Vitamins
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.
June 26, 2012 Total slides : 120 55
56. Vitamins & Cofactors Anemia & Vitamins
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.
June 26, 2012 Total slides : 120 56
57. Vitamins & Cofactors Anemia & Vitamins
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.
June 26, 2012 Total slides : 120 57
58. Vitamins & Cofactors Anemia & Vitamins
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.
June 26, 2012 Total slides : 120 58
59. Vitamins & Cofactors Anemia & Vitamins
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.
June 26, 2012 Total slides : 120 59
60. Vitamins & Cofactors Anemia & Vitamins
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
June 26, 2012 Total slides : 120 60
61. Vitamins & Cofactors Anemia & Vitamins
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.
June 26, 2012 Total slides : 120 61
63. Vitamins & Cofactors 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
Sore mouth and tongue
Pallor
June 26, 2012 Total slides : 120 63
66. Vitamins & Cofactors Anemia & Vitamins
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.
June 26, 2012 Total slides : 120 66
67. Vitamins & Cofactors Anemia & Vitamins
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.
June 26, 2012 Total slides : 120 67
68. Vitamins & Cofactors Anemia & Vitamins
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.
June 26, 2012 Total slides : 120 68
70. Vitamins & Cofactors 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.
June 26, 2012 Total slides : 120 70
71. Vitamins & Cofactors Anemia & Vitamins
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.
June 26, 2012 Total slides : 120 71
72. Vitamins & Cofactors Anemia & Vitamins
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.
June 26, 2012 Total slides : 120 72
73. Vitamins & Cofactors Anemia & Vitamins
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.
June 26, 2012 Total slides : 120 73
74. Vitamins & Cofactors Anemia & Vitamins
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.
June 26, 2012 Total slides : 120 74
77. Vitamins & Cofactors Anemia & Vitamins
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).
June 26, 2012 Total slides : 120 77
78. Vitamins & Cofactors Anemia & Vitamins
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..
June 26, 2012 Total slides : 120 78
80. Vitamins & Cofactors 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.
June 26, 2012 Total slides : 120 80
81. Vitamins & Cofactors Anemia & Vitamins
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.
June 26, 2012 Total slides : 120 81
82. Vitamins & Cofactors Anemia & Vitamins
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.
June 26, 2012 Total slides : 120 82
83. Vitamins & Cofactors Anemia & Vitamins
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.
June 26, 2012 Total slides : 120 83
85. Vitamins & Cofactors 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.
June 26, 2012 Total slides : 120 85
86. Vitamins & Cofactors Anemia & Vitamins
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.
June 26, 2012 Total slides : 120 86
88. Vitamins & Cofactors Anemia & Vitamins
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.
June 26, 2012 Total slides : 120 88
89. Vitamins & Cofactors Anemia & Vitamins
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.
June 26, 2012 Total slides : 120 89
91. Vitamins & Cofactors Anemia & Vitamins
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%).
June 26, 2012 Total slides : 120 91
92. Vitamins & Cofactors Anemia & Vitamins
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)
June 26, 2012 Total slides : 120 92
94. Vitamins & Cofactors Anemia & Vitamins
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.
June 26, 2012 Total slides : 120 94
96. Vitamins & Cofactors 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.
June 26, 2012 Total slides : 120 96
97. Vitamins & Cofactors Anemia & Vitamins
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
megaloblastic anemia.
Vitamin C possibly prevent hemolysis resulting from
compromised celluar antioxidant defence mechanism.
June 26, 2012 Total slides : 120 97
98. Vitamins & Cofactors Anemia & Vitamins
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.
June 26, 2012 Total slides : 120 98
99. Vitamins & Cofactors Anemia & Vitamins
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.
June 26, 2012 Total slides : 120 99
103. Vitamins & Cofactors 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.
June 26, 2012 Total slides : 120 103
104. Vitamins & Cofactors Anemia & Vitamins
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 .
June 26, 2012 Total slides : 120 104
105. Vitamins & Cofactors Anemia & Vitamins
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
June 26, 2012 Total slides : 120 105
107. Vitamins & Cofactors Anemia & Vitamins
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.
June 26, 2012 Total slides : 120 107
109. Vitamins & Cofactors 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.
June 26, 2012 Total slides : 120 109
111. Vitamins & Cofactors Anemia & Vitamins
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.
June 26, 2012 Total slides : 120 111
112. Vitamins & Cofactors Anemia & Vitamins
Mechanism of OA action
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.
June 26, 2012 Total slides : 120 112
113. Vitamins & Cofactors Anemia & Vitamins
Mechanism of OA action
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,
June 26, 2012 Total slides : 120 113
115. Vitamins & Cofactors Anemia & Vitamins
PABA
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.
June 26, 2012 Total slides : 120 115
116. Vitamins & Cofactors Anemia & Vitamins
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.
June 26, 2012 Total slides : 120 116
117. Vitamins & Cofactors Anemia & Vitamins
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
June 26, 2012 Total slides : 120 117
118. Vitamins & Cofactors Anemia & Vitamins
Vitamin D
June 26, 2012 Total slides : 120 118
119. Vitamins & Cofactors Anemia & Vitamins
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.
June 26, 2012 Total slides : 120 119
120. Vitamins & Cofactors Anemia & Vitamins
Laetrile
Relationship between laetrile and anemia…
What is your idea?
June 26, 2012 Total slides : 120 120
June 26, 2012 Conspicuous= آشکار،هویدا Speculative= قابل تعمق
June 26, 2012 Among the more obscure causes of megaloblastic anemia is the acronymic curiosity thiamine-responsive megaloblastic anemia (TRMA), subject of an article by Boros and colleagues (page 3556 ). The use of mass spectrometry in conjunction with stable isotope-labeling techniques has made it possible to unlock doors along previously inaccessible hallways of gene function analysis in the metabolomic maze. The door to TRMA was thus opened by Boros et al, who have pioneered the use of stable isotope-based dynamic metabolic profiling (SIDMAP) as a key to better understanding of changes in substrate flow as a basis for drug mechanisms and disease. Teaming up with the Boston group who first identified the loss of function mutation in the high-affinity, low-capacity thiamine transporter in TRMA, the authors have pinpointed the cause of disruption of nucleic acid synthesis that leads ultimately to premature apoptosis in this intriguing genetic disorder. Through tracking the stable 13 C-labeled glucose in fibroblasts from patients with TRMA, these authors 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. Use of the powerful tools provided by SIDMAP and related techniques that use even more sensitive accelerator mass spectrometry with ultra-low-dose labeling techniques provides the promise to address, perhaps in vivo, similar unanswered questions involving the molecular basis for disease. Applying these methods to the study of the more common conditions that cause megaloblastic anemia, but that are still shrouded in mystery, could ultimately shed similar light on their mechanism. Ralph Green University of California at Davis References Wickremasinghe RG, Hoffbrand AV. Reduced rate of DNA replication fork movement in megaloblastic anemia. J Clin Invest. 1980;65: 26-36. [Medline] [Order article via Infotrieve] Goulian M, Bleile B, Tseng BY. The effect of methotrexate on levels of dUTP in animal cells. J Biol Chem. 1980;255: 10630-10637. [Abstract/ Free Full Text] Koury M, Horne D. Apoptosis mediates and thymidine prevents erythroblast destruction in folate deficiency anemia. Proc Natl Acad Sci U S A. 1994;91: 4067-4071. [Abstract/ Free Full Text]
June 26, 2012 Ameliorates = بهبود یافتن
June 26, 2012 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.
June 26, 2012 Babinski reflex: Alternative Names Reflex - Babinski's; Extensor plantar reflex Definition Return to top Babinski's reflex occurs when the great toe flexes toward the top of the foot and the other toes fan out after the sole of the foot has been firmly stroked. This is normal in younger children, but abnormal after the age of 2. Considerations Return to top Reflexes are specific, predictable, involuntary responses to a particular type of stimulation. Babinski's reflex is one of the infantile reflexes. It is normal in children under 2 years old, but it disappears as the child ages and the nervous system becomes more developed. In people more than 2 years old, the presence of a Babinski's reflex indicates damage to the nerve paths connecting the spinal cord and the brain (the corticospinal tract). Because this tract is right-sided and left-sided, a Babinski's reflex can occur on one side or on both sides. An abnormal Babinski's reflex can be temporary or permanent. Causes Return to top Generalized tonic-clonic seizure (there may be a temporary Babinski's reflex for a short time after a seizure ) Amyotrophic lateral sclerosis Brain tumor (if it occurs in the corticospinal tract or the cerebellum) Familial periodic paralysis Friedreich's ataxia Head injury Hepatic encephalopathy Meningitis Multiple sclerosis Pernicious anemia Poliomyelitis (some forms) Rabies Spinal cord injury Spinal cord tumor Stroke Syringomyelia Tuberculosis (when it affects the spine) Home Care Return to top Typically, a person (older than an infant) who has a Babinski's reflex will also have incoordination , weakness , and difficulty with muscle control. Safety is important to prevent the risk of injury. The person may need assistance with activity, and the environment should be kept free of hazards. When to Contact a Medical Professional Return to top This finding is usually discovered by the health care provider, and the affected person usually is not aware of its presence. What to Expect at Your Office Visit Return to top The medical history will be obtained and a physical examination performed. Medical history questions will be asked documenting this reflex in detail. The physical examination will probably include a complete nervous system (neurologic) examination. Diagnostic testing may include: MRI scan of the head or MRI scan of the spine Angiography of the head Somatosensory evoked potentials Lumbar puncture and analysis of the cerebrospinal fluid --------------------------------
June 26, 2012 Bone marrow aspiration: Alternative Names Iliac crest tap; Sternal tap Definition Bone marrow is the tissue that makes blood cells. It is found in the hollow part of most bones. Bone marrow aspiration is the removal of this tissue for examination. See also: Bone marrow biopsy Bone marrow culture How the Test is Performed The health care provider will take the bone marrow from your pelvic or breast bone. (Occasionally, another bone is selected.) First, the area is cleaned with a germ-killing medicine, then numbing medicine (local anesthesia) is applied. Next, the health care provider inserts a special needle into the bone. The needle has a tube attached to it, which creates suction. A small sample of bone marrow fluid flows into the tube. The needle is removed. A laboratory specialist looks at the bone marrow fluid under a microscope. How to Prepare for the Test No special preparation is necessary for this test. How the Test Will Feel There will be a prick and a slight burning sensation with the local anesthetic. Pressure may be felt as the needle is inserted into the bone. There is a sharp sucking sensation as the marrow is aspirated, which lasts for only a few moments. Why the Test is Performed This test is used to diagnose leukemia, infections, some types of anemia , and other blood disorders. It may help determine if cancers have spread. Normal Results The marrow should contain blood-forming (hematopoietic) cells, fat cells, and connective tissues. What Abnormal Results Mean Abnormal results may be due to: Acute lymphocytic leukemia Acute nonlymphocytic leukemia (AML) Anemia of B-12 deficiency Anemia of folate deficiency Chronic lymphocytic leukemia (CLL) Chronic myelogenous leukemia (CML) Idiopathic thrombocytopenic purpura (ITP) Lymphoma Macroglobulinemia of Waldenstrom Megaloblastic anemia Multiple myeloma Myelofibrosis Pernicious anemia Primary thrombocytopenia Risks There may be some bleeding at the puncture site. More serious risks, such as serious bleeding or infection, are very rare. References Hoffman R, Benz EJ, Shattil SS, et al. Hematology: Basic Principles and Practice . 4th ed. Orlando, Fl: Churchill Livingstone; 2005:2656-2657. Behrman RE. Nelson Textbook of Pediatrics. 17th ed. Philadelphia, Pa: WB Saunders; 2004; 1695-1697.
June 26, 2012 Schilling test: Alternative Names Return to top Vitamin B12 absorption test Definition Return to top The Schilling test is used to determine whether the body absorbs vitamin B12 normally. How the Test is Performed Return to top You will get two doses of vitamin B12 (cobalamin). The first dose is radioactive and taken by mouth. The second dose is not radioactive and is given as a shot 2 - 6 hours later. The injection of vitamin B12 may sting. Your urine will then be collected over the next 24 hours to measure whether you are absorbing vitamin B12 normally. This test may be performed in four different stages to find the cause of low vitamin B12 levels. Stage I is as described above. If Stage I is abnormal, Stage II may be done 3 - 7 days later. In Stage II, you'll receive radioactive B12 along with intrinsic factor. Intrinsic factor is produced in the stomach and attaches (binds) to vitamin B12. Stage II of the test can tell whether low vitamin B12 levels are caused by problems in the stomach that prevent it from producing intrinsic factor. If a Stage II test is abnormal, a Stage III test is performed. In the Stage III test, the Stage II test is repeated after you have taken antibiotics for 2 weeks. This can tell whether abnormal bacterial growth has caused the low vitamin B12 levels. A Stage IV test determines whether low vitamin B12 levels are caused by problems with the pancreas. With this test, you will take pancreatic enzymes for three days, followed by a radioactive dose of vitamin B12. A 24-hour urine sample is needed. For adults: On day 1, urinate into the toilet after getting up in the morning. Collect all of your urine (in a special container) for the next 24 hours. On the morning of day 2, urinate into the container after getting up. The test is now complete. Cap the container. Keep it in the refrigerator or a cool place. Label the container with your name, the date, and the time you last urinated, and return it as instructed. For infants: Thoroughly wash the area around the area from which urine exits the body (urethra). Open a urine collection bag (a plastic bag with an adhesive paper on one end), and place it on your infant. For males, place the entire penis in the bag and attach the adhesive to the skin. For females, place the bag over the labia. Place a diaper over the infant (including the bag). Check the infant often and change the bag after the infant has urinated into it. For active infants, this procedure may take a couple of attempts -- lively infants can displace the bag, making it difficult to get the urine sample. Drain the urine into the container. Deliver the container to the laboratory or your health care provider as soon as possible after you've collected all of the urine. How to Prepare for the Test Return to top Fast (you can drink water) for 8 hours before starting the test, then eat normally for the next 24 hours. The health care provider may ask you to stop taking drugs that can affect the test. You cannot have parenteral (intramuscular injection) B12 within 3 days before the exam. If the collection is being taken from an infant, you may need to use a couple of extra urine collection bags. How the Test Will Feel Return to top The injection of vitamin B12 may sting. Why the Test is Performed Return to top The Schilling test is performed to check vitamin B12 absorption. Intrinsic factor is produced in the stomach and is required for vitamin B12 absorption. If your body does not make intrinsic factor, you cannot absorb vitamin B12. The lack of intrinsic factor can lead to low levels of vitamin B12 because of pernicious anemia, partial removal of the stomach (gastrectomy), poor vitamin B12 absorption due to bowel disease, too much bacteria in the intestine, a lack of enough enzymes being produced by the pancreas, or certain medications. The Schilling test is most commonly used to evaluate patients for pernicious anemia. The test can be falsely positive. Most of the time this is due to poor urine collection. Other reasons include kidney disease or problems with the lining of the small intestine. Normal Results Return to top Urinating 8 - 40% of the radioactive vitamin B12 within 24 hours is normal. What Abnormal Results Mean Return to top Low vitamin B12 levels can cause pernicious anemia. This can occur if you have problems absorbing vitamin B12 or you don't eat enough foods that contain vitamin B12. Some other causes are removal of part of the stomach or the development of an antibody against intrinsic factor. If there is a problem with the stomach's ability to make intrinsic factor, Stage I of the test will be abnormal and Stage II will be normal. Both the Stage I and II Schilling tests will be abnormal in people who have problems absorbing vitamin B12 and intrinsic factor in the small intestine. Abnormal Stage I and II Schilling tests may indicate: Biliary disease Celiac disease (sprue) Hypothyroidism Liver disease Lower-than-normal amounts of vitamin B12 absorption may indicate: Biliary disease, resulting in poor absorption (malabsorption) of nutrients from the intestinal tract Intestinal malabsorption (for example, related to sprue or celiac disease) Liver disease (causing malabsorption) Pernicious anemia Additional conditions under which the test may be performed: Anemia of B12 deficiency Blind loop syndrome Megaloblastic anemia Risks Return to top Local reaction to vitamin injection Nausea Feeling lightheaded
June 26, 2012 LDH: Alternative Names Lactate dehydrogenase; Lactic acid dehydrogenase Definition Return to top LDH is a blood test that measures the amount of lactate dehydrogenase (LDH). See also: LDH isoenzymes How the Test is Performed Return to top 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. How to Prepare for the Test Return to top Your health care provider may ask you to stop taking drugs that may affect the test. Drugs that can increase LDH measurements include anesthetics, aspirin, clofibrate, fluorides, mithramycin, narcotics, and procainamide. Why the Test is Performed Return to top LDH is most often measured to check for tissue damage. The enzyme LDH is in many body tissues, especially the heart, liver, kidney, skeletal muscle, brain, blood cells, and lungs. LDH affects the chemical reaction for the conversion of pyruvate and lactate . Exercising muscles convert (and red blood cells metabolize ) glucose to lactate. Lactate is released into the blood and is later taken up by the liver. The liver converts lactate back to glucose and releases glucose into the blood. Resting muscles, red blood cells, and other tissues then take up this glucose. Normal Results Return to top Normal values may vary slightly from one lab to another. A typical range is 105 - 333 IU/L (international units per liter). What Abnormal Results Mean Return to top Higher-than-normal levels may indicate: Cerebrovascular accident (CVA, stroke) Heart attack Hemolytic anemia Low blood pressure Infectious mononucleosis Blood deficiency (intestinal ischemia) Liver disease (for example, hepatitis ) Muscle injury Muscular dystrophy New abnormal tissue formation (neoplastic) states Pancreatitis Tissue death (pulmonary infarction) If the LDH level is raised, your doctor may order an LDH isoenzymes measurement. Other conditions under which the test may be done: Anemia of vitamin B-12 deficiency Megaloblastic anemia Pernicious anemia References Return to top Abeloff MD, Armitage JO, Niederhuber JE, Kastan MB, McKenna WG. Clinical Oncology . 3rd ed. Philadelphia, Pa: Churchill Livingstone, 2004. Ferri FF. Ferri's Clinical Advisor 2007 . Philadelphia, Pa: Mosby, 2006.
June 26, 2012 Abstract There is evidence that vitamin A benefits hematopoiesis and iron metabolism. For this reason, we investigated the relationship of serum retinol concentration to hemoglobin concentration and biochemical indicators of iron status in Canadian aboriginal infants. No infant had biochemical evidence for vitamin A deficiency (serum retinol 0.35 mol/L) although 25.6% had anemia (hemoglobin 110 g/L) and 20.4% had iron deficiency (serum ferritin 10 g/L). Serum retinol concentration was significantly correlated with hemoglobin concentration (r 0.30, p 0.001, n 185) and serum iron concentration (r 0.44, p 0.001, n 166) but not with serum ferritin concentration. Anemic infants had lower serum retinol concentrations than those without anemia (1.09 0.33 mol/L vs. 1.36 0.36 mol/L, p 0.01). Infants given vitamin supplements that contained vitamin A, ascorbic acid, and vitamin D3 had a higher hemoglobin concentration than infants not given supplements (117 11 vs. 113 10 g/L, p 0.04) and a lower prevalence of anemia (21.9% vs. 37.0%, p 0.05). In conclusion, vitamin A was positively associated with hemoglobin concentration in this pediatric populatio
June 26, 2012 Abstract As part of a pig study to elucidate the interactions between low v itamin A status and helminth infections, surprisingly, we obser v ed higher haemoglobin le v els and packed cell v olumes in the pigs with low v itamin A status. A possible haemoconcentration effect, due to some disturbance in the regulation of the extracellular fluid v olume, could lead to underestimation of the pre v alence of anaemia in v itamin A deficient human populations. Therefore, this phenomenon needs to be further clarified in studies in v ol v ing determination of plasma v olumes. # 2002 Published by Elsevier Science B.V.
June 26, 2012 Vitamin E deficiency in the premature infant is associated with a hemolytic anemia. This anemia responds to tocopherol and the response is characterized by a rise in the hemoglobin and a fall in the reticulocyte count. Treatment of premature infants from birth wih supplemental vitamin E reduces the severity of anemia and prevents the marked reticulocytosis commonly observed in these infants of low birth weight. Vitamin E deficiency in the rat results in the appearance of a mild compensated hemolytic process. This is accompanied by thrombocytosis. The erythrocytes demonstrate increased pentose phosphate pathway activity. Tocopherol appears to be poorly absorbed from a low-fat diet in the premature infant. In infants with vitamin E deficiency there appears to be an increase in the creatine-to-creatinine ratio, lower serum proteins, and an increased excretion of methylmalonic acid in the absence of vitamin B 12 deficiency. The interrelationship of this potpourri of observations remains to be explained.
June 26, 2012 . Figure 1 illustrates some of the basic features of iron metabolism and erythropoiesis, emphasizing points in the process at which certain vitamins may influence iron deficiency and anaemia. Vitamins such as vitamin A, folic acid, vitamin B 12 , riboflavin and vitamin B 6 , are necessary for the normal production of red blood cells, while others such as vitamins C and E protect mature red blood cells from premature destruction by free radical oxidation ( Table 2 ). Riboflavin, vitamin A and vitamin C may also prevent anaemia by improving intestinal absorption of iron, or by facilitating its mobilization from body stores. This paper explores the effects of these vitamins in the treatment and prevention of anaemia in human populations and identifies areas for future research.
June 26, 2012 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 B 12 deficiency. The best response occurred in a patient with postgastrectomy pernicious anemia. Little effect was seen in two undernourished patients who responded well, nevertheless, to B 12 therapy. Irregularity in the absorption of this poorly soluble compound from the intestinal tract, possible changes en route, and other limiting nutritional factors may account for some variation in response. Preparations suitable for parenteral administration have not been developed. The early effects of orotic acid in pernicious anemia resembled those of small amounts of B 12 . Reticulocytosis appeared 7 to 14 days after the start of therapy. Gradual clinical and hematologic improvement followed. We have not been able to evaluate the possible ability of this compound to reverse the neurologic manifestations of pernicious anemia. Complete remissions in the disease were never produced, however, by orotic acid, for at the height of improvement, red cell macrocytosis and some degree of megaloblastic cellular development persisted in the bone marrow. Patients maintained on orotic acid alone for 5 to 7 months gradually relapsed with increasing anemia and lingual mucosal atrophy. Toxic effects of the chemical were not seen. 10 In no instance did it produce an effect in pernicious anemia like that of folic acid: a quick but suboptimal response at first, followed ultimately by relapse, with neurologic disease, lingual mucosal atrophy, and/or anemia with a hypocellular nonmegaloblastic bone marrow—all comparatively refractory at this stage to vitamin B 12 therapy. Since orotic acid is known to function only as an intermediate in the synthesis of pyrimidines 2, 9 (fig. 12), the hematopoietic effects of some precursors and derivatives of the compound were studied. None proved to be as active as orotic acid. Carbamyl aspartic acid given in doses of 3 Gm. daily was followed by a slight reticulocytosis in two patients. Aspartic acid given in doses up to 15 to 20 Gm./day with 3 to 6 Gm. of orotic acid had little or no effect in two patients. A concentrate of uridylic and cytidylic acids obtained from yeast, probably absorbed from the intestinal tract as nucleosides, showed some effect in one of the two patients to whom it was given. This same preparation was remarkably effective when given to a child with a congenital abnormality in pyrimidine biosynthesis who excreted large amounts of orotic acid in the urine. 13 The parenteral administration of thymidine, 0.5 Gm. daily for six days, had no hematopoietic effect in one patient, but a significant response occurred when inosine was given with it concurrently. Sodium deoxyribonucleic acid (DNA) prepared from fish sperm by the hot alkaline extraction method produced a moderate reticulocytosis in one patient. A second crest followed the addition of orotic acid to her regimen. A less hydrolyzed DNA preparation given to another patient for one week had no effect, but there was apparently none either when orotic acid was given 6 Gm./day for the same length of time. Vitamin B 12 and folic acid appear to have similar, overlapping or reciprocal, actions in different biologic systems. A comparison of the hematologic effects of folic acid metabolites with that of orotic acid was accordingly undertaken. Methionine reduces the vitamin B 12 requirement of bacteria, and the de novo synthesis of this amino acid is increased by cobalamin. 14-16 Methionine given to patients with pernicious anemia in relapse, however, seemed to depress hematopoiesis. It is of interest that the methyl group of methionine is not utilized for the biosynthesis of thymine in bacteria. The methyl group of thymine was derived from glucose instead. 17 The hematopoietic effect of serine has not yet been studied in patients with pernicious anemia in relapse. Histidine, which is synthesized by folic acid containing enzymes, was given with the thought that it might become an &quot;essential&quot; amino acid under some circumstances, or provide a general source of active formate or of transferable formimino groups usable in protein and/or nucleic acid synthesis, 16,18 A definite hematopoietic stimulus was obtained from DL-histidine in two Patients with pernicious anemia in relapse. The response was quick and suboptimal, however, and did not potentiate that of orotic acid. One patient in partial hematologic remission after taking histidine for 12 weeks was then given folic acid. Additional benefit was not observed. Further studies of the effect of these and other folic acid metabolites in pernicious anemia and in nutritional megaloblastic anemia are in progress. Biochemical studies in the past have given no indication that vitamin B 12 is concerned with pyrimidine biosynthesis. The latter process, of considerable current interest also in reference to the development of pyrimidine antimetabolites, is outlined in figure 12. 19-23 Carbamyl phosphate and aspartic acid are converted by known enzymatic reactions to orotic acid. The latter is rapidly converted to pyrimidine nucleotides, derivatives, and to the pyrimidine moieties of nucleic acids. Hurlbert and Potter injected small amounts of orotic acid intraperitoneally into rats. 19 About one-third of the chemical was immediately excreted unchanged and another third immediately taken up by the liver. Orotic acid was quickly converted in the liver quantitatively to acid-soluble metabolites, particularly uridine-5'-phosphate, derivatives of this compound, and cytidine-5'-phosphate. The uridine phosphate pool appeared to be the immediate metabolic precursor of the uracil of the ribonucleic acid (RNA) in the nucleus and a major source of the pyrimidines of the cytoplasmic RNA. A large contribution to liver DNA pyrimidine was observed in tissue regenerating after partial hepatectomy. 24 Thymidine is formed in vitro from uracil deoxyriboside by a reaction inhibited by Aminopterin. 25 Vitamin B 12 may facilitate nucleoside and nucleic acid synthesis by different mechanisms in different biologic systems. In bacteria there is evidence that it promotes the synthesis of methionine, nucleosides and/or deoxyribose, and possibly activates protein sulfhydryl groups. 14 In animals it may promote methyl group neogenesis, but there is increasing doubt that it has anything to do with transmethylation. 16,26 The indications are that vitamin B 12 has different function(s) than that of folic acid, which is concerned in the synthesis, transfer and/or incorporation of formate, formimino and hydroxymethyl groups. The vitamin B 12 requirement of the human adult on a weight basis is 10 to 15 times less than that of animals, 26 but a disease unique to man, pernicious anemia, results from its lack. Evidence relating the deficiency in pernicious anemia to pyrimidines was first obtained by Vilter and associates who reported incomplete hematologic remissions in patients to whom they gave 15 to 30 Gm. of thymine or uracil daily. 11, 12 Thymine was effective in two of their patients who had relapsed while taking folic acid. Uracil had no effect in a patient with megaloblastic anemia of pregnancy, but who did respond to thymine. Nieweg, et al., studied the relationship of vitamin B 12 to folic acid in the megaloblastic anemias. They cited evidence to support the idea that in the human, vitamin B 12 was particularly concerned with pyrimidine formation and RNA-protein synthesis. 27 The degree of remission that can be produced in patients with pernicious anemia in relapse by the administration of orotic acid suggests, too, that one major consequence of vitamin B 12 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, 28 however, there are too many ways by which orotic acid could influence metabolism in the presence of vitamin B 12 deficiency to justify further speculation.
June 26, 2012 TO THE EDITOR: Anemia is not usually mentioned as a complication of vitamin D intoxication but has been described in patients with and without renal failure [1] . We report on a woman with vitamin D intoxication and anemia not caused by renal failure. A 66-year-old woman was admitted to the emergency department with hypercalcemia diagnosed after 3 weeks of severe constitutional symptoms. Three years earlier, osteoporosis had been diagnosed and a rheumatologist had prescribed an extemporaneous formulation (200 IU of vitamin D and 1 g of calcium glucobionate twice daily), which was prepared by a pharmacist. Blood tests at admission showed a calcium level of 4.04 mmol/L, a hemoglobin concentration of 103 g/L, a urea concentration of 11.2 mmol/L, and a creatinine level of 146 µmol/L. After rehydration, the hemoglobin concentration decreased to 83 g/L. Anemia was nonspecific and nonregenerative, and results of additional tests (chest radiography, mammography, abdominal ultrasonography, bone scintigraphy, fibrogastroscopy, and colonoscopy) were normal. Parathyroid hormone was undetectable, and the plasma 25-hydroxyvitamin D level was 696 nmol/L (normal range, 15 to 125 nmol/L). Two months later, while the patient was receiving a milk-free diet, plasma 25-hydroxyvitamin D levels were high, serum calcium levels were normal, and anemia had resolved. Symptoms had begun roughly when a new bottle of pills with a vitamin D content of 200 µg (8000 IU) was started. 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 [2] or act through high calcium levels, which inhibit erythroid colony formation in vitro [3] and erythropoietin production in vitro [4] and in vivo [5] . 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. 1. Scharfman WB, Proop S. Anemia associated with vitamin D intoxication. N Engl J Med. 1956; 255:1207-12. 2. Reichel H, Koeffler HP, Norman AW. Production of 1a,25-dihydroxyvitamin D3 by hematopoietic cells. Prog Clin Biol Res. 1990; 332:81-97. 3. Misiti J, Spivak JL. Erythropoiesis in vitro. J Clin Invest. 1979; 64:1573-9. 4. Nagakura K, Ueno M, Brookins J, Beckman BS, Fisher JW. Effects of low calcium levels on erythropoietin production by human renal carcinoma cells in culture. Am J Physiol. 1987; 253:797-801. 5. McGonigle RJ, Brookins J, Pegram BL, Fisher JW. Enhanced erythropoietin production by calcium entry blockers in rats exposed to hypoxia. J Pharmacol Exp Ther. 1987; 241:428-32.