This document discusses folic acid and vitamin B12 deficient anemias. It begins by defining anemia and describing different types including blood loss anemia, aplastic anemia, and hemolytic anemia. It then focuses on megaloblastic anemias which are caused by folic acid or vitamin B12 deficiencies. The roles of folic acid and vitamin B12 in hematopoiesis and their absorption pathways are explained. Pernicious anemia, a type of megaloblastic anemia caused by vitamin B12 deficiency due to lack of intrinsic factor, is described in more detail. Diagnosis and treatment of folic acid and vitamin B12 deficiencies are also summarized.

1. Folic acid & B12 Deficient Anemia,
By
Dr.Liniyanti D.Oswari,MNS.,MSc
For block 8
Medical School, University of Sriwijaya

2. Learning Objective
• Understand of the Hematopoesis
• Understand the Metabolism of folic acid
Cyanocobalamine in Erythropoesis.
• Understand the etiology and the
management of Anemia.

3. Anemia
• Anemia means a decrease in
hemoglobin content,
• or RBCs count,
• or both of them below the normal
range.
• Anemia leads to a decrease in blood
ability to transport oxygen to tissue
cells.

4. • Types & causes of anemia:
I-Blood loss anemia:
A-Acute blood loss anemia:
 Due to severe hemorrhage.
 Plasma volume is replaced rapidly by the fluids
present in tissue spaces.
 This leads to marked dilution of the blood.
 RBCs are replaced within 2-3 weeks.
 Sufficient iron gives normocytic cells but
insufficient iron will produce microcytic RBCs.
Anemia

5. • Types & causes of anemia:
I-Blood loss anemia:
B-Chronic blood loss anemia:
 Due to repeated loss of small amounts of blood
over a long period e.g.:
-Gastrointestinal bleeding (peptic ulcer)
-Excessive menstruation.
-Hemorrhagic diseases.
 Due to depletion in iron stores the newly formed
RBCS are microcytic.
Anemia

6. Types & causes of anemia:
II-Aplastic anemia:
It results from destructione of bone marrow.
 It may result from:
1-Excessive exposure to x-rays or gamma rays.
2-Chemical toxins e.g. cancer therapy & prolonged
exposure to insecticides or benzene.
3-Invasion of bone marrow by cancer cells.
4-Following infection by hepatitis.
 Damaged bone marrow don’t produce any RBCs, so in
aplastic anemia RBCS are
normocytic.
 It is associated with decrease in WBCs & platelets.
Anemia

7. Anemia
Types & causes of anemia:
III-Hemolytic anemia:
It results from increased rate of destruction of RBCs inside
the cardiovascular system.
 Causes of hemolytic anemia:
A-Hereditary:
1-Membrane abnormalities.
2-Enzyme deficiency e.g. G-6-P Dehydrogenase.
3-Hemoglobin abnormalities.
B-Acquired:
1-Incompatible blood transfusion.
2-Parasitic infection e.g. malaria.
3-Toxic agents e.g. snake venom & insect poisons.
4-Thermal e.g. several burns.

8. Anemia
Types & causes of anemia:
IV-Dyshemopoietic anemia: Which may be due to:
1-Iron deficiency anemia.
2-Maturation failure (megaloblastic) anemia:-
a-Vitamin B12 deficiency.
b-Folic acid deficiency.
3-Anemia of endocrine disorders.
4-Nutritional anemia.
5-Anemia of renal failure.

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

10. MEGALOBLASTIC ANEMIA

11. MEGALOBLASTIC (Macrocytic)
ANEMIA
• High MCV
• High MCH
• Normal MCHC
• Macrocytic Anemia
• Megaloblastic : defective DNA synthesis
• Non-megaloblastic : numerous
mechanisms

12. Nutritional Requirements for
Hematopoiesis
• Metals : iron copper cobalt
• B12 and Folate
• Other vitamins: B6, A, E, C
• Riboflavin, Niacin

13. Megaloblastic Anemias
• A form of anemia characterized by the
presence of large, immature, abnormal red
blood cell progenitors in the bone marrow
• 95% of cases are attributable to folic acid or
vitamin B12 deficiency

14. N N
N
N
CH 3
CH 3
H2NCOCH 2CH 2
H3C
H2NCOCH 2
CH 2CONH 2
H2NCOCH 2
CH 3
H2C
CH 2CH 2CONH 2
CH 3
CH 3
CH 2
N
H
O
CH 2CONH 2
O
H3C
P
O
O
O
OH
HO
N
N
CH 3
CH 3
Co
CN
CH 3
H3C
H
VITAMIN B 12
corin nucleus
benzylimidazole
cobalt coordinated

15. Vitamin B12
• Source : food of animal origin
- liver
- muscle
- eggs
- cheese and milk
- Not in plants
- Made by bacteria

16. B12 Absorption
• 1. Release from food sources gastric
proteases and acids
• 2. Binding by salivary cobalophilins
• 3. Digestion of cobalophilin-B12
complex by pancreatic enzymes
• 4. Binding to intrinsic factor (IF)
• IF is secreted by gastric parietal cells
• 5. Attachment of B12-IF to receptors
• 6. Endocytosis and binding to
transcobalamin II

17. B12 Dependant Reactions
• 1. Synthesis of methionine from
• homocysteine requires : B12 and folate
• 2. Synthesis of succinyl CoA from
• methyonyl CoA requires :
• methylmalonyl CoA mutase

19. FOLIC ACID
Sources : synthesized by plants
• and microorganisms
• Vegetables, fruits, dairy products
• Polyglutamated
• Thermo labile

20. Folic Acid Absorption-Transport
• 1. Polyglutamates converted to mono-
glutamates Intestinal carboxypeptidase
• 2. Binding of monoglutamates to brush
border receptor
• 3. Conversion to methyltetrahydrofolate
during absorption
• 4. Bind to serum protein
• 5. Receptor mediated cell uptake
• 6. Polyglutamated in cytoplasm

21. Untuk
Sintesa DNA

23. Pernicious Anemia
An Autoimmune Disease
• Antibodies against :parietal cells
intrinsic factor (IF)
• Thyroid - myxedema
• Melanosomes - vitiligo

24. Pernicious Anemia
Hematologic features :
• anemia
• Pancytopenia (trombosit turun, leukosit
turun)
• megaloblastic hematopoiesis
• cellular bone marrow
• ineffective hematopoiesis

27. Folate Deficiency
• Hematologic features : same as
Pernicious Anemia.
• Clinical Picture : no neurologic findings

28. Folate Deficiency :Diagnosis
• Dietary history
• Clinical conditions:
pregnancy
malabsorption (sprue)
hemolytic anemia (paling sering)
drugs
• Laboratory:
serum or red cell folate levels

29. Pernicious Anemia
Presenting Complaint
• Symptoms of anemia : 58%
• Sensory paresthesis :13%
• GI complaints :11%
• Sore tongue or mouth : 7%
• Weight loss : 5%
• Difficulty walking : 3%
• Other :3%

30. Pernicious Anemia - Diagnosis
• History and Physical
• Glossitis (radang pada lidah)
• Pallor (pucat)
• neurologic exam
• Laboratory
• blood smear (schilling test)
• antibody assays
• B12 level
• Other
• Schilling test

31. Schilling Test
• First stage :
• 1. Inject B12 IM (1,000 ug) to saturatetranscobalamin II
• 2. Administer oral B12 - radiolabeled
• 3. Collect 24 h urine
• 4. Measure radioactivity in urine
• Second stage :
• 1. Inject B12 IM (1,000 ug) to saturate transcobalamin II
(Same as 1st stage)
• 2. Administer oral B12 – radiolabeled plus intrinsic
factor (HOG)
• 3. Collect 24 h urine, (Same as 1st stage)
• 4. Measure radioactivity in urine,(Same as 1st stage)

32. Static Test for Folate/B12 Status
Folate
• Measured in whole blood (plasma and
cells) and then in the serum alone
• Difference is used to calculate the red
blood cell folate concentration (may
better reflect the whole folate pool)
• Can also test serum in fasting patient
B12
• Measured in serum

33. Functional Tests for
Macrocytic Anemias
• Homocysteine: Folate and B12 are
needed to convert homocysteine to
methionine; high homocysteine may
mean deficiencies of folate, B12 or B6
• Methylmalonic acid measurements
can be used along with homocysteine
to distinguish between B12 and folate
deficiencies (↑ in B12 deficiency)
• Schilling test: radiolabeled cobalamin
is used to test for B12 malabsorption

34. Pernicious Anemia
A macrocytic, megaloblastic anemia caused by a
deficiency of vitamin B12.
• Usually secondary to lack of intrinsic factor (IF)
• May be caused by strict vegan diet
• Also can be caused by ↓gastric acid secretion,
gastric atrophy, H-pylori, gastrectomy, disorders
of the small intestine (celiac disease, regional
enteritis, resections), drugs that inhibit B12
absorption including neomycin, alcohol,
colchicine, metformin (obat DM), pancreatic
disease

35. Symptoms of
Pernicious Anemia
• Paresthesia (especially numbness and
tingling in hands and feet)
• Poor muscular coordination
• Impaired memory and hallucinations
• Damage can be permanent

36. Vitamin B12 Depletion
• Stage I—early negative vitamin B12 balance
• Stage II—vitamin B12 depletion
• Stage III—damaged metabolism: vitamin B12
deficient erythropoiesis
• Stage IV—clinical damage including vitamin
B12 anemia
• Pernicious anemia—numbness in hands and
feet (matirasa pada tgn kaki); poor muscular
coordination; poor memory; hallucinations

37. Causes of Vitamin B12
Deficiency
• Inadequate ingestion
• Inadequate absorption
• Inadequate utilization
• Increased requirement
• Increased excretion
• Increased destruction by antioxidants

38. Treatment of B12 Deficiency
• Before 1926 was incurable; until 1948 was
treated with liver extract
• Now treatment consists of injection of 100 mcg
of vitamin B12 once per week until resolved,
then as often as necessary
• Also can use very large oral doses or nasal gel
• MNT: high protein diet (1.5 g/kg) with meat, liver,
eggs, milk, milk products, green leafy vegetables

39. Pernicious Anemia
Treatment
• B12 by IM injection
• Frequent at first
• Monthly thereafter life long

40. Folic Acid Deficiency
• Tropical sprue; pregnancy; infants born to
deficient mothers
• Alcoholics
• People taking medications chronically that affect
folic acid absorption
• Malabsorption syndromes

41. Causes of Folate Deficiency
• Inadequate ingestion
• Inadequate absorption
• Inadequate utilization
• Increased requirement
• Increased excretion
• Increased destruction
• Vitamin B12 deficiency can cause
folate deficiency due to the methylfolate
trap

42. Methylfolate Trap
• In the absence of
B12, folate in the
body exists as 5-
methyltetrahydro-
folate (an inactive
form)
• B12 allows the
removal of the 5-
methyl group to form
THFA

43. Stages of Folate Depletion and
Deficiency
• Stage I—early negative folate balance
(serum depletion)
• Stage II—negative folate balance (cell
depletion)
• Stage III—damaged folate metabolism
with folate-deficient erythropoiesis
• Stage IV—clinical folate deficiency
anemia

44. Diagnosis of Folate Deficiency
• Folate stores are depleted after 2-4
months on deficient diet
• Megaloblastic anemia, low leukocytes
and platelets
• To differentiate from B12, measure
serum folate, RBC folate (more
reflective of body stores) serum B12
• High formiminoglutamic acid (FIGLU)
in the urine also diagnostic

45. Hemolytic Anemia
• Oxidative damage to cells—lysis occurs
• Vitamin E is an antioxidant that seems to be
protective.
• This anemia can occur in newborns, especially
preemies.

46. Nonnutritional Anemias
• Sports anemia (hypochromic
microcytic transient anemia)
• Anemia of pregnancy: dilutional
• Anemia of inflammation, infection, or
malignancy (anemia of chronic
disease)
• Sickle cell anemia
• Thalassemias

47. Sports Anemia
• Transient—usually in athletes who are runners;
from compression of RBCs in feet until they
burst (biru-biru (?)), releasing hemoglobin
• Check lab values
• Counsel about a proper diet

48. References
• First Known Heart Attack Associated With Beta- thalassemia Major
Reported." Heart Disease Weekly February 22, 2004: 10.
• Bowden, Vicky R., Susan B. Dickey, and Cindy Smith Greenberg. Children
and Their Families: The continuum of care . Philadelphia: W.B. Saunders
Company, 1998.
• "Thalassemias." In Principles and Practice of Medical Genetics , Volume 2,
edited by Alan E.H. Emery, MD, PhD, and David L. Rimoin, MD, PhD. New
York: Churchill Livingstone, 1983.
• Thompson, M.W., R. R. McInnus, and H. F. Willard. Thompson and
Thompson Genetics in Medicine , Fifth Edition. Philadelphia: W.B. Saunders
Company, 1991.
• Olivieri, N. F. "The Beta Thalassemias." The New England Journal of
Medicine 341 (1999): 99-109.