By DR.

ANU JOSEPH
MD Part – I
Fr. Muller’s HMC
DEFINITION
 Anemia is defined as decreased oxygen carrying capacity
of blood due to a hemoglobin concentration in the blood
below the lower limit of the normal range for the age and
sex of the individual
 Normal values:
AGE Hb% RANGE

Adult male 14.5 g/dl 13.5-17 g/dl

Adult female 12.5 g/dl 11.5-15.5 g/dl

Newborns 23 g/dl 18-23 g.dl

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HAEMATOPOIESIS
The pluripotent stem cells in the bone
marrow give rise to two types of
multipotent stem cells :

 Non – Lymphoid Stem Cells

 Lymphoid Stem Cells

The Non-lymphoid stem cells form

the circulating Erythrocytes,
Granulocytes, Monocytes and
Platelets. The lymphoid cells form
B and T lymphocytes of the
immune system
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Classification OF ANEMIA
 PATHOPHYSIOLOGIC:
1. Anemia due to increased blood loss

a) Acute post hemorrhagic anemia

b) Chronic: Due to lesion of gastro intestinal
tract, gynecologic disturbances .

2. Anemia due to impaired red cell production

a) Cytoplasmic maturation defects

I) Defective heme synthesis: Fe, deficiency
anemia
ii) Defective globin synthesis: Thalassemias
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b) Nuclear maturation defects
i) Vitamin B12 or folic acid deficiency:
Megaloblastic anemias.

c) Defect in stem cell proliferation and differentiation.

i) Aplastic anemia
ii) Pure Red cell aplasia

d) Anemia of Chronic disorders

i) Anemia of Infections
ii) Anemia of Renal disease.
iii) Anemia of Liver disease.
iv) Endocrinopathies
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e) Bone marrow Infiltration
i) Leukemias
ii) Lymphomas.
iii) Multiple sclerosis.
iv) Multiple Myeloma.

f) Congenital Anemia
i) Sideroblastic Anemia
ii) Congenital Dyserythropoietic anemia

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3) Anemias due to increased Red cell
destruction

a) Intracorpuscular defect (Hereditary and acquired)

b) Extra corpuscular defect (acquired hemolytic anemia's)

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CLASSIFICATION OF ANEMIA
B). Morphologic

Based on Red cell

Size,
Hb content &
Red cell Indices

Microcytic
Hypochromic Normocytic
Normochromic Macrocytic
MCV, MCH, MCHC
are reduced. MCV, MCH, MCHC Normochromic
are normal. MCV is Raised
Eg. Fe def Anemia, Eg. Acute Blood loss Eg. Megaloblastic anemia
Thalassaemia, Hemolytic Anemias
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Chronic disease
PATHOPHYSIOLOGY
 Subnormal level of Hb causes lowered O2 carrying capacity
of blood, this inturn initiates compensatory adaptations such
as
a. Increased oxygen release from Hb.
b. Increased Blood flow to tissues.
c. maintenance of blood flow
d. Redistribution of Blood flow to
maintain the cerebral blood supply

As a result tissue Hypoxia develops causing impaired

functioning of tissues. Tissues with high O2 requirement such
as heart, CNS, Skeletal Muscles during exercise bear the
brunt of clinical effects of anemia.
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 CLINICAL MANIFESTATIONS OF ANAEMIA
Development of signs and symptoms of anaemia depends on
following factors:

I. The speed of onset of anaemia

II. The severity of anaemia
III. The age of the patient

SYMPTOMS:
 Easy fatiguability, tiredness, lethargy
 Generalised muscular weakness, headache
 Confusion
 Exertional Dyspnoea

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SIGNS:
1. Pallor: of mucous membranes, conjunctiva and skin
2. CVS: tachycardia, collapsing pulse, exertional dyspnoea,
cardiomegaly, midsystolic flow murmur
3. CNS: attacks of faintness, giddiness, drowsiness,
numbness and tingling sensations of the hands and feet,
headache, tinnitus.
4. Ocular : retinal haemorrhage
5. Reproductive system: amenorrheoa or menorrhagia, loss
of libido.
6. Renal system: mild protienuria, impaired concentrating
capacity of kidney in sever anemia
7. Gastro intestinal system: anorexia, flatulence, nausea,
constipation, weight loss.
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INVESTIGATIONS
After obtaining detailed history pertaining to different
general and specific symptoms and signs , inorder to
confirm or deny the diagnosis of anemia, the following
plan of investigations is generally followed.

A) Hb gm % estimation
B) Peripheral blood examination:
Examination is done for certain morphological
features after staining it with Romanowsky dyes
(Leishmann stain, Jener-Giemsa stain etc).

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 The features may be
a)Variation in size of RBC (Anisocytosis)
b)Variation in shape of RBC (poikilocytosis)
c) Inadequate Hb formation.
d)Compensatory erythrocyte formation
e)Miscellaneous changes

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a) VARIATION IN SIZE (ANISOCYTOSIS)

 Mean diameter of red cell is-7.2m

 Presence of cells with larger diameter-
Macrocytosis.
 Presence of cells with smaller diameter-
Microcytosis.
 Presence of both types - Dimorphic

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MACROCYTES:
 Mainly in Megaloblastic Anemia
& also in
a) Aplastic anemia occasionally
b) Chronic liver diseases
c) Condition with increased erythropoiesis

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MICROCYTES:
 Fe deficiency Anemia
 Thalassemia
 Spherocytosis
 Hemolytic Anemia (Fragmentation of
erythrocytes)

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b) VARIATION IN SHAPE (POIKILOCYTOSIS)

 Megaloblastic anemia
 Thalassemia
 Myelosclerosis
 Iron deficiency anemia
 Microangiopathic hemolytic anemia

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c) INADEQUATE Hb FORMATION
 The intensity of Hb staining in a smear gradually
decreases from periphery to center.
Hypochromasia: - Increased central pallor.
 Iron deficiency Anemia
 Thalassemia
 Sideroblastic Anemia

Hyperchromasia:- Deep pink staining of red cells.

 Megaloblastic Anemia
 Spherocytosis
 Neonatal blood
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d) COMPANSATORY ERYTHROPOIESIS

i) Polychromaisa: Red cells have more than one type of

colour.

ii) Normoblastemia: Presence of naked cells in the

peripheral blood film.
 Normally found in small no in case of cord blood at birth
 Found in large numbers in hemolytic diseases of new
born, Extramedullary erythropoisis, Splenectomy.

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iii) Punctuate basophilia: Diffuse & uniform basophilic granularity
in the cell. Seen in:
 Aplastic Anemia
 Thalassemia
 Myelodyplasia
 Infections and lead poisoning

iv) Howell-Jolly Bodies: Purple nuclear remnants usually found

singly. Seen in:
 Megaloblastic Anemia
 After Splenectomy.

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e) MISCELLANEOUS CHANGES

 Abnormal Red blood cells found:

1) Spherocytosis :- Spheroidal rather than the biconcave disc-
shaped cell.
 Hereditary Spherocytosis

 Autoimmune hemolytic anemia

 ABO hemolytic diseases of the new born

2)Schistocytosis:- Fragmentation of erythrocytes

 Thalassemia
 Megaloblastic Anemia.

 Iron deficiency anemia

 Hemolytic anemia and sever burns

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3) Sickle cells: RBC’s are sickle shaped Known as Sickle cell
Anemia.
4) Target cells: Unusually thin cells (leptocyte) in which
there is central round stained area & peripheral rim of
Hb.
 Iron deficiency Anemia
 Thalassemia
 After splenectomy
5) Burr cells: Fragments having one or more spines.
 Seen in Uremia
6) Crenated red cells: erythrocytes which develop
numerous projections from surface. Seen due to alkaline
pH, presence of fatty substance on the slide or in cases
where film is made of blood that has been allowed to
stand overnight.
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C) RED CELL INDICES
 High MCV & MCH - (macrocytic, hyperchromic)
 Pregnancy, B12/folate deficiency , liver disease,
hypothyroidism, MDS

 Low MCV & MCH - (microcytic, hypochromic)

 Iron deficiency, Thalassaemia

 Normal MCV & MCH - (normocytic, normochromic)

 Acute blood loss
 Hemolytic anemia

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D)Leucocyte & Platelet count

 It helps to distinguish pure anemia from Pancytopenia

in which Red cells granulocytes & platelets are
reduced.

 In anemias due to hemolysis or haemorrhage,

neutrophil and platelet counts are often elevated.

 In infections and leukemia, leucocytes counts are high

& immature leucocytes appear in blood

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E) Reticulocyte count

 (Normal 0.5 to 2.5 %)

 In acute hemorrhage and hemolysis the reticulocyte
response indicates impaired marrow function.
 Reticulocytes are absent in aplastic anemia

F) ESR
 Usually gives a clue to the underlying organic disease but
sometimes anemia itself may cause a rise in ESR.

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G) Bone marrow examination

1. Bone marrow aspiration

 Salah’s bone marrow aspiration needle
 Romanowsky dye staining
 Gives an idea about
o Cellularity
o Details of developing cells
o Storage diseases
o Presence of foreign cells such as neoplastic cells
o Fungi( histoplasmosis), parasitic infestation(malaria,
leishmaniasis)
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2. Trephine biopsy
 Jamshidi- trephine needle is used
 Provides an excellent view of overall marrow architecture,
cellularity and presence or absence of infiltrates

3. Perl’s staining
 Used to detect iron stores in marrow
 Prussian blue reaction is present

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 FACTS ABOUT IRON
 Iron deficiency is the commonest cause of anaemia the world
over.
 Total body iron content is in the range of 2 gm in women and
up to 6gm in men.
 Loss of iron from body per day is in the range of 1 mg for an
adult male and ranges between 1.5 mg to 2 mg in an adult
female in reproductive age.
 Daily requirement of iron is
 Adult male: 0.5 to 1 mg
 Adult female: 1-2 mg
 12- 15 yrs of age : 1- 2.5 mg
 Pregnancy : 1.5 – 2.5 mg
 infants : 1 mg
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 ABSORPTION OF IRON
Average content of iron in diet is 15-20 mg of iron, of which
only 5-10 mg is normally absorbed.

Iron is absorbed mainly in duodenum and proximal jejunum.

Two forms of iron are available for absorption: haem iron and
non haem iron

Haem iron is mainly from red or organ meats

Non haem iron is mainly from cereals and other vegetables

Haem iron is better absorbed than non haem iron

Ferrous form is better absorbed than ferric form.

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 ABSORPTION OF NON HAEM IRON
o Released as ferrous or ferric form.
o Absorbed as ferrous form.
o Reduction when required takes place at the brush
border by ferrireductase.
o Transport across the membrane by divalent
metal transporter 1 (DMT 1)
o Inside the gut cells, ferric iron may be stored as
ferritin or further transported to transferrin by
two vehicle proteins – ferroportin and hephaestin
HAEM IRON ABSORPTION is not yet
clear.
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Absorption of non-haem iron may be enhanced by factors
such as ascorbic acid (vitamin C), citric acid, amino acid,
sugars, gastric secretions and HCl.

Absorption is impaired by factors like medicinal antacids,

milk, pancreatic secretions, phytates, phosphates,
ethylene diamine tetra-acetic acid (EDTA) and tannates
containing in tea.

A fraction of Iron that enters the mucosal cells are lost

with exfoliation of cells.

Iron is stored in the body as:

ferritin : liver, spleen, BM and skeletal muscle
haemosiderin : RE cells.
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 REGULATION OF ABSORPTION
Absorption is influenced by:
 Erythroid hyperplasia even with normal or increased iron
stores.
 Anaemias with ineffective erythropoeisis.
 Iron deficiency.
Maintenance of Iron Balance:
 Largely by regulating the absorption of dietary Fe.
 Hepcidin inhibits Fe uptake in the duodenum as well as Fe
release from macrophages.
 Fe excretion is limited to the 1-2 mg lost daily by shedding of
mucosal & skin epithelial cells.

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TRANSPORT

 In plasma, bound to a β-globulin, Transferrin,

which is systhesised in the liver
 Transferrin-bound iron is made available to the
marrow where iron is utilised for haemoglobin
synthesis.
 Transferrin is reutilised after iron is released from
it.

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DISTRIBUTION OF IRON
Haemoglobin – present in RBCs
(65%)
Myoglobin – muscles (3.5%)
Haem and Non-haem enzymes –
e.g. cytochrome, catalase,
peroxidases, succinic
deydrogenase and flavoproteins
(0.5%)
Transferrin-bound iron – plasma
(0.5%)
(all these are functional forms)
Ferritin and haemosiderin –
storage form of excess iron
(30%) – stored in mononuclear-
phagocyte cells of the spleen,
liver and bone marrow and in
the parenchymal cells of liver.
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 Major Iron Compartments
 Metabolic
 Hemoglobin 1800-2500 mg
 Myoglobin 300-500 mg
 Storage
 Iron storage 0-1000 mg
 Transit
 Serum iron 3 mg

 Total 3000-4000 mg

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EXCRETION
 Desquamation of epithelial cells from the GIT
 Excretion in the urine and sweat
 Loss via hair and nails
 Iron excretion by faeces mainly consists of unabsorbed
iron and desquamated mucosal cells.
 Additional 0.5- 1 mg per day, is lost in menstruating
women.

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PATHOGENESIS OF IDA
IDA develops when the supply of iron is inadequate to
meet with the requirement, for haemoglobin synthesis.

The development of iron deficiency depends upon one

or more of the following factors :
Increased blood loss
Increased requirements
Inadequate dietary intake
Decreased intestinal absorption

(varies according to age & sex; developed and

developing countries)
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 ETIOLOGY

INCREASED INADEQUATE
INCREASED DECREASED
BLOOD DIETARY
REQUIREMENTS ABSORBTION
LOSS INTAKE

INFANCY, POOR PARTIAL OR

UTERINE CHILDHOOD ECONOMIC COMPLETE
ADOLESCENCE STATUS GASTRECTOMY

ANOREXIA IN
GIT PREMATURITY
PREGNANCY
ACHLOROHYDRIA

PREGNANCY
ELDERLY INTESTINAL
RENAL &
INDIVIDUALS MALABSORBTION
LACTATION

NOSE

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PATHOLOGY
Pathological changes progress through 3 main stages.
I. IRON STORE DEPLETION
 Serum Fe may remain normal but serum ferritin levels
may be affected.
II. IRON DEFICIENT ERYTHROPOIESIS
 Serum Fe lowers
 Anemia is not yet developed
 Hb, MCV, MCH levels remain unaffected
III.IRON DEFICIENCY ANAEMIA
 Frank anaemia develops
 Cells are hypochromic and microcytic
 Hb, MCH, MCV levels lowered
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CLINICAL FEATURES
ANAEMIA
Weakness, fatigue, dysponea on exertion, palpitation and
pallor of skin, mucus membrane and sclerae
EPITHELIAL TISSUE CHANGES
( In long standing cases)
Nails – koilonychia or spoon shaped nails
Thinning of hair
Plummer-Vinson syndrome or Patterson Kelly
Syndrome
Tongue – atropic glossitis
Dysphagia – because of development of thin
membranous webs at the post cricoid area

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SYSTEMIC MANIFESTATIONS OF IRON
DEFICIENCY
 Behavioral and  Esophageal webs and strictures
neuropsychiatric
manifestations
 Pica (pagophagia)
 Angular stomatitis

 Koilonychia

 Glossitis

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INVESTIGATIONS
IDA progresses in three stages
Storage iron depletion
Iron deficient erythropoisis
Frank iron deficiency anaemia

A.Blood picture and red cell indices

Hb gm percentage decreased
Red cells – microcytic, hypochromic
Reticulocyte count – normal or decreased
Absolute values – MCV, MCH, MCHC, all decreased
Leucocytes and platelets – normal
Poikilocytosis and anisocytosis
Presence of target cells
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B. Bone marrow findings
Marrow cellularity – increased
Erythropoeisis – increased normoblasts(erythroid
hyperplasia)
Other cells – normal
Marrow iron – decreased or absent iron stores

C. Biochemical findings
Serum iron level – decreased
Total iron binding capacity - increased
Serum ferritin – decreased
Serum transferrin receptors – increased
Transferrin saturation((serum Fe/TIBC)×100) -
decreased
Red cell protoporphyrin
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- decreased 51
BLOOD FILM

 Hypochromic, microcytic with particular cell

shapes

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TREATMENT
 CORRECTION OF THE DISORDER

 CORRECTION OF IRON DEFICIENCY

1. Oral therapy – ferrous sulphate
2. Parental therapy –
1. Iron dextran (imferon)

2. Iron sorbitol citrate (jectofer)

3. Iron gluconate

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APLASTIC ANEMIA
 Defined as pancytopenia associated with
hypocellularity of bone marrow.
 There may be:
o Reduction in the number of pluripotent stem
cells
o Fault in those remaining cells
o Immune reaction against the remaining stem
cells preventing the repopulation of BM
 Failure of only one cell line may also occur
resuting in isolated deficiencies such as the absence
of red cell precursors – pure red cell aplasia.
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ETIOLOGY

Inherited : Fanconi’s Anemia

• Autosomal recessive disorder caused by defects in
component of multi protein complex required for DNA
repair
• Accompanied by multiple congenital anomalies like
hypoplasia of Kidney, spleen & bone often involving
thumb or radii

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ACQUIRED
a) Idiopathic
 Primary stem cell defect

 Immune mediated

b) Chemical agents/ drugs

 Dose related
o Chemotherapeutic drugs, NSAIDs, alkylating agents,

antimetabolites, benzene etc.

 Idiosyncratic reaction
o Myelotoxic or nonmyelotoxic drugs( aplasia severe,

irreversible and fatal)

c) Physical agents
 Radiations (damages the DNA)

 Heavy metals like gold, arsenic, bismuth), insecticides

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d) Viral Infections
 Seronegative Hepatitis, cytomegalo virus, Epstein
barr virus, Herpes vearicella zoster, HIV
e) Immunologic diseases
 Transfusion associated graft-versus- host disease

 SLE

 Eosinophilic fascitis

f) Miscellaneous
 AA may occur very rarely during pregnancy &
resolve with delivery or with spontaneous/induced
abortion

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PATHOGENESIS
2 major possibilities have been invoked

I. An immunologically mediated suppression:

• Stem cells may be first antigenically altered by
exposure to drugs, infectious agents or other
environmental insults.
• This evokes cellular immune responses
• Activated T-cells produce cytokines such as TNF
and interferon
• This prevent stem cell growth and development
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 II. An intrinsic abnormality of stem cells:
 Some marrow insult presumably causes
genetic damage
 This limits the proliferative and
differentiative capacity of stem cells

 Genetically altered stem cells might also express

neo-antigens that could serve as target for T-cell
attack.

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MORPHOLOGY

 Hypocellular bonemarrow devoid of

hematopoietic cells.
 Only fat cells, fibrous stroma and scattered foci
of lymphocytes & plasma cells remain
 Marrow aspirate often yields little material –
“A dry tap”

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CLINICAL COURSE

HISTORY
 It can occur in any age & sex.
 Onset is usually insidious
 History: of prior drug use, chemical exposure,
preceeding viral infection.
 Family history of haematological disease

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MANIFESTATIONS
 Anemia: progressive weakness, pallor, shortness of
breath
 Thrombocytopenia: easy bruising, oozing from gums,
nose bleeding, heavy menstrual flow, Petechiae &
Ecchymoses.
 Granulocytopenia: frequent & persistent minor
infections or sudden onset of chills, fever &
prostration
 Splenomegaly is absent; if present diagnosis is
seriously questioned.
 Symptoms are restricted to haematologic system
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 Physical examination:

 Petechiae and ecchymoses

 Retinal haemorrhages
 Blood in stool, cervical bleeding
 Pallor of skin & mucous membranes
 Café au lait spots & short stature may point out
Fanconi’s anaemia.
 Peculiar nails & leukoplakia indicates
dyskeratosis congenita.

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INVESTIGATION
 BLOOD SMEAR
 Anaemia
• Hb: reduced
• Normocytic and normochromic cell

• Sometimes macrocytosis

• Reticulocytes are absent

 Leukopenia
• Absolute granulocyte count: reduced

 Thrombocytopenia
• Platelet count : reduced

 BONE MARROW
 Dry tap (empty BM)
 Replacement by fat
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BONE MARROW
BIOPSY

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DIAGNOSIS
 Bone marrow biopsy.
 Peripheral Blood examination.

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TREATMENT
I. CORRECTION OF UNDERLYING CAUSE
I. BONE MARROW TRANSPLANTATION
 Patient < 40 yrs of age
 Patient with HLA- identical sibling
I. IMMUNO-SUPPRESSIVE THERAPY
 Patient > 40 yrs of age
 Patient without HLA- identical sibling
I. SUPPORTIVE TREATMENT
 Avoidance & prompt treatment of infections
 Platelet & RBC transfusion

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PROGNOSIS

 WITHDRAWAL OF TOXIC DRUGS LEAD TO RECOVERY

IN SOME CASES
 SPONTANEOUS REMISSIONS IN IDIOPATHIC CASES
 IN YOUNGER PATIENTS ALLOGENIC BONE MARROW
OFFERS SCOPE.

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MEGALOBLASTIC ANEMIA

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MEGALOBLASTIC ANEMIA
 Disorders caused by the impaired DNA synthesis that
are characterised by nuclear maturation defect in the
haematopoietic precursors in the BM.
 Maturation of nucleus is delayed relative to that of
cytoplasm
 As a result abnormal cells (megaloblasts) are formed
which are usually larger in size (macrocyte)
 Defective DNA synthesis is due to lack in vit B12/folic
acid
 Deficiency of vit B12/ folic acid
 Defective metabolism of vit B12/ folic acid
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TYPES OF MEGALOBLASTIC
ANEMIA

 Anemia due to deficiency of vit B12

 Pernicious anemia
 Anemia due to folate deficiency

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VITAMIN B12
 SOURCES
 Foods of animal origin
such as kidney, liver,
heart, muscle meat,
fish, egg, milk, cheese
 Synthesized by
intestinal bacteria but
are not absorbed from
there.

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 Daily requirement : 2-4micro gram
 Body stores : 2- 3 mg ( enough for 2-4 years)
 Site of absorption : ileum

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ABSORPTION & TRANSPORT
In stomach vit B12 binds with gastric R Binder

In duodenum pepsin releases vit B12 and this then binds

with Intrinsic Factor

In distal ileum, this complex binds to brush border

receptors and enters the mucosal cells

In mucosal cells, vit B12 is released and transferred to

transcobalamine II

Transcobalamine II- vit B12 complex then enters portal

circulation liver, BM, other cells
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STORAGE
 Liver stores about 2 mg of vit B12
 Kidney, heart and brain together store about 2 mg of
vit B12
 Combined storage of body is adequate for 2- 4 years
 Lost through bile & shedding of intestinal epithelial
cells
 Major part of excreted vit B12 is reabsorbed in the
ileum by the IF and hence entero-hepatic circulation
is maintained

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ROLE OF VIT B12
 Vit B12 is present in body as two major forms
 Methyl cobalmine
 Adenosyl cobalmine
 Both act as coenzymes in two main biochemical
functions
 Required for
 methylaton of homocysteine to methionine
 Conversion of methyl malonyl Co A to succinyl Co A

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FOLIC ACID
 Exists in conjugated form, polyglutamate form
 Active form is tetrahydrofolate form
 Daily requirement : 100- 200 micro gram
 Destroyed by cooking

 SOURCES
 Plants: fresh green leafy vegetables, fruits and cereals
 Animal tissues: liver, kidney and to a lesser extent,
muscle meats and milk

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ABSORPTION & TRANSPORT
 Folate is absorbed from duodenum and upper jejunum.
Some amounts from lower jejunum and ileum.
 Folate is present as polyglutamate in food stuffs.
 Polyglutamate folate conjugase mono &
diglutamates
reduced in
mucosal
cells
THF methyl Tetrahydrofolate(THF)
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STORAGE

 Mainly stored in liver and red cells

 Total body store in 10- 12 mg ( enough for 4
months)
 Lost through sweat, urine, faeces and saliva

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ROLE OF FOLIC ACID
 Acts as coenzyme in 2 main biochemical
reactions
 Thymidylate synthetase formation: formation
of deoxy thymidylate monophosphate (dTMP)
from deoxy uridylate monophosphate (dUMP)
 Methylation of homocysteine to methionine

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ETILOGY OF MEGALOBLASTIC ANEMIA
I. Vitamin B12 deficiency
A. Inadequate dietary intake
B. Malabsorption
1. Gastric causes: pernicious anemia, gastrectomy,
congenital lack of IF, achlorhydria, CA
2. Intestinal causes: tropical sprue, ileal resection,
crohn’s disease, neoplasms, competition for vit.
B12, drugs that block the absorption
II. Folate deficiency
A. Inadequate dietary intake
B. Malabsorption: jejunal resection, tropical sprue,
crohn’s disease etc.
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 A. Excess demand
1. Physiological: pregnancy, lactation, infancy
2. Pathological: malignancy, tuberculosis, chronic
exfoliative skin disorders, rheumatoid arthritis
etc
B. Excess urinary folate loss

I. Other causes
A. Impaired metabolism:drugs that inhibit
dihydrofolate reductase, alcohol, congenital
enzyme deficiency
B. Idiopathic
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PATHOGENESIS
Folic acid deficiency Vit B12 deficiency

Impaired synthesis of Impaired homocysteine –

dTMP from dUMP methionine reaction

Impaired synthesis of Folic acid is trapped in its

DNA as dTMP is a transport form ( not
precursor in DNA converted to active
synthesis tetrahydro folate form)

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PATHOLOGY
 Nuclear – cytoplasmic maturation asynchrony
 Abnormal cells are formed (megaloblasts)
 Cells become arrested in development & die within the
marrow (ineffective erythropoiesis)
 Bone marrow will have hypercellularity
 Hemolysis occurs
 Erythroid hyperplasia
 Because of these maturational derangement
there is an accumulation of megaloblast in the bone
marrow, yielding too few erythrocytes hence the
anaemia.
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CLINICAL FEATURES
1. Anemia : insidious and gradually progressing,
weakness, lethargy, pallor0
2. Glossitis : smooth, beefy, red tongue
3. Neurological symptoms( vit B12 deficiency):
numbness, paraesthesia, weakness, ataxia,
diminished reflexes(demyelination of peripheral
nerves)
4. Mild jaundice, angular stomatitis, pupura,
symptoms of malabsorption, weight loss and anorexia

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INVESTIGATIONS
 Hb: reduced
 Blood smear:
 macrocytic hyperchromic or normochromic
 Macro ovalocytes
 Reticulocytes reduced or absent
 Anisocytosis , poikilocytosis
 Occassional normoblast
 MCV & MCH: increased
 MCHC : normal/ reduced
 Leucocytes : reduced, hypersegmented neutrophils seen
 Platelets :moderately reduced
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 Bone marrow:
 Hypercellularity
 Erythroid hyperplasia
 Megaloblasts : abnormal, large, nucleated erythroid
precursors
 Nuclear – cytoplasmic maturation asynchrony
 Ineffective erythropoiesis : presence of degenerated
erythroid precursors
 Marrow iron : increased
 Biochemical values
 Serum unconjugated bilirubin: increased
 Serum lactate dehydrogenase: increased
 Serum iron and ferritin: normal/ increased
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 Tests for vit B12 deficiency
 Serum vit B12 : Reduced
 Schilling test
 Serum methylmalonic acid: Increased
 Homocysteine : Elevated
 Test for folate deficiency
 Serum folate : Reduced
 Red cell folate : Reduced
 Serum methylmalonic acid : Normal
 Homocysteine : Elevated
 Urinary excretion of formimino glutamic acid:
Increased
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 Schilling test
 First stage:
 Oral dose of radioactively labelled vit B12 (hot B12)
 Large Parenteral dose of unlabelled vit B12 (cold
B12)
Result I Result II
More than 7% lower quantity of oral B12
of oral B12 excreted excreted in urine
in urine
test repeated with IF
Normal individual (second stage)
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 Secod stage

IF is administered along with hot B12

Result I Result II
Urine excretion of decreased urine excretion
Hot B12 is normal/ of hot B12
increased
Than before

IF deficiency mal-absorption of vit

B12
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PERNICIOUS ANEMIA

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 PERNICIOUS ANEMIA

 Disorder characterised by deficiency of Intrinsic

factor due to atrophy of gastric mucosa, resulting in
vit B12 deficient megaloblastic anemia.
 autoimmune reaction against parietal cells result in
atrophy
 Incidence is higher in patients with other autoimmune
diseases such as grave’s disease, thyroiditis etc.

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PATHOGENESIS
 Immunologically mediated – auto immune –
destruction of gastric mucosa

Chronic atrophic gastritis

Loss of parietal cells

Deficiency of intrinsic factor

Deficient absorption of vit B12

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 Three types of antibodies are found.
Type I: blocking Ab
:blocks vit B12 – IF binding
:found in serum and gastric juice
Type II: binding Ab
:prevent binding of IF or IF-Vit B12
:complex to its ileal receptor.
Type III: parietal canalicular Ab
:localize in the microvilli of the canalicular
:system of the gastric parietal cell.
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PATHOLOGY
 Alimentary system
 Atrophy of fundic glands
 Parietal cells are virtually absent
 Intestinalisation: glandular lining epithelium will
be replaced by mucus secreting goblet cells
 Megaloid alterations in some cells
 Central nervous system
 Myelin degeneration of spinal cord
 Bone marrow

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CLINICAL FEATURES

 Anemia
 Glossitis
 Neurological manifestations

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INVESTIGATIONS

 Same as that of megaloblastic anemia

 Hb
 Blood smear
 Bone marrow
 Biochemical values
 Schilling test

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TREATMENT

 CORRECTION OF DEFICIENCY
 CORRECTION OF UNDERLYING
PATHOLOGY

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