MEGALOBLASTIC ANEMIA

Macrocytic anemias are divided into

 Megaloblastic anemias
 Non megaloblastic anemias
The megaloblastic anemias are macrocytic anemias associated
with an abnormality in the maturation of haematopoietic cells in the
bonemarrow.
The 2 major cause are
 Folate deficiency
 Vita B12 deficiency

In vitamin B12 or folate deficiency anemia megaloblastosis result from interference

in folic acid and vitamin B12 independent nucleic acid synthesis in the immature
erythrocyte.

DHF REDUCTASE
DNA

DHF <

THF

5, 10-MTHF

Active B 12 Dietary B12

NUCLEIC
ACID PRECURSORS

Dietary folate deficiency&conversion


 5-MTHF

Dietary folates are absorbed in this process and converted (A) to 5-methyl
tetrahydrofolate, which is then converted viaB12-dependent reaction (B) to
tetrahydrofolate (C).
After gaining a carbon,tetrahydrofolate is converted to a folate cofactor
(D), 5,10- methyl-tetrahydrofolate, used by thymidylate synthetase (E) in the
biosynthesis of nucleic acids. The 5,10-methyl-tetrahydrofolate cofactor is
converted to dihydrofolate (F) during biosynthesis. Normally,dihydrofolate
reductase reduces dihydrofolate back to tetrahydrofolate (C), which can again pick
up a carbon and be recycled to produce more 5,10-methyl-tetrahydrofolate (D).

Megaloblastic anemias is due to abnormality in DNA metabolism

resulting from a deficiency in vit B 12 or folate,as well as due to various drugs such
as

 HYDROXY UREA
 ZIDOVUDINE
 CYTOSINE ARABINOSIDE
 METHOTREXATE
 AZATHIOPRINE
 6-MERCAPTOPURINE

Features of megaloblastic anemia

 Glossitis
 Angular stomatitis
 Altered bowel habit
Anorexia
 Mild jaundice
 Sterility
 Fever
VITAMIN B12 DEFICIENCY ANEMIA

Vitamin B12 deficiency anemia is due to deficiency in vit B 12.This is more common
in women.3 major causes of vitB12 deficiency are

 Inadequate utilization


  Inadequate intake
 Malabsorption syndromes

Vitamin B12 deficiency may result from overgrowth of bacteria in the bowel that
use vitB12 or from injury or removal of ileal receptor sites where vit B 12 and
intrinsic factor complex are absorbed.Blind loop syndrome,Whipple
syndrome,zollinger-Ellison syndrome,Tapeworm infection,inflammatory bowel
disease all may contribute to the development of vitamin B 12 deficiency.

Inadequate dietary consumption of vit B 12 is rare.It is usually occurs only in

patients who are strict vegetarians and their brest fed infants,chronic alcoholics.

Decresed vit B 12 absorption is seen in patients with pernicious

anemia ,which is caused by the absence of intrinsic factors due to autoimmune
destruction of gastric parietal cells,atrophy of the gastric mucosa,or stomach
surgery.

Clinical Manifestations of vitamin B12 anemia

Psychatric manifestations

 Impaired mental state

 Delirium
 Psychosis
 Depression

Neurological manifestations

 Tingling or numbness in fingers and toe

 Difficulty waIking
 Mood changes or depression
 Memory loss,Disorientation
 Dementia

PHYSIOLOGICAL IMPORTANCE OF VITAMIN B12

 Vit B12, also known as cobalamin,is crucial for DNA synthesis in cells
undergoing rapid turn over,such as haematopoietic and enteric lining cells.


  It is also vital to optimal function of the immune system
 B12 is stored in the liver,but it can take 5 to 10 years for a person to become
B12 deficient due to malabsorption.

PATHOPHYSIOLOGY

Vitamin B12 is necessary forDNAsynthesis, is important in metabolic reactions

involving folic acid, and is essential in maintaining the integrity of the neurologic
system.
After the stomach’s acidic environment
facilitates the breakdown of vitamin B12 bound to food, the vitamin B12 binds to
the intrinsic factor released by the stomach’s parietal cells. The secretion of
intrinsic factor generally corresponds to the release of hydrochloric acid and serves
as a cell-directed carrier protein similar to transferrin for iron. This complex,
resistant to degradation,forms in the duodenumand allows for subsequent
absorption of vitamin B12 in the terminal ileum. The cobalamin-intrinsic factor
complex is taken up into the ileal mucosal cell, the intrinsic factor is discarded, and
the cobalamin is transferred to transcobalamin II, which serves as a transport
protein.This complex is secreted into the circulation and is taken up by the liver,
bone marrow, and other cells. Transcobalamin II has a short half-life of 1 hour and
is rapidly cleared from the blood. Consequently,most circulating cobalamin is
bound to serum haptocorrins (formerlytranscobalamin I and transcobalamin III)
whose function is unknown. However, it should be noted that an alternate pathway
for vitamin B12 absorption independent of intrinsic factor or an intacterminal
ileum accounts for a small amount of vitamin B12 absorption.50 This alternate
pathway involves passive diffusion and accounts for approximately 1% absorption
of the ingested vitamin B12.
LABORATORY FINDINGS

 In macrocytic anemias ,MCV is usually elevated to 110 to 140 FL,but some

patients deficient in vit B12 may have a normal MCV.
 Incresaed methyl malonic level are a sensitive indicator of mild vitB 12
deficiency and elivated homocysteine levels denote vit B 12 or folate
deficiency.
 Seum iron concentration and transfrrin saturation are usually
elevated,although iron levels may be low in some patients with pernicious
anemia.
 Serum lactate dehydrogenase and indirect bilirubin levels may elevated as a
result of heamolysis.


  Other findings include Reticulocye count low,low serum vit B 12
level(<100pg/ml).

SCHILLING TEST

The patient first receives an oral dose of radiolabeled vitamin B12.

Two hours later, the patient receives a large intramuscular dose of
nonlabeled vitamin B12 to saturate plasma transport proteins. Any excess vitamin
B12 that is not taken up by the transport proteins or stored in the liver will be
excreted in the urine. A 24-hour urine collection is then measured for radioactivity.
If sufficient gastrointestinal intrinsic factor is being produced, the radiolabeled B12
will be absorbed.
If oral absorption is impaired, part 2 of the test is conducted 5 to
7 days later. The second stage of the Schilling test differentiates inadequate
secretion of intrinsic factor by the stomach from an abnormality in absorption by
the ileum. Radiolabeled vitamin B12 is administered orally with a sufficient
amount of intrinsic factor. Results within the normal range indicate that the defect
is in the production of intrinsic factor as opposed to other causes of vitamin B12
deficiency such as dietary deficiency or small bowel pathology. Generally,
abnormal results for stage 1 followed by a normal result in stage 2 is consistent
with pernicious anemia.
If the results in part 2 are still low, then the third stage of the
test is conducted to determine whether the cause of the deficiency
is due to bacterial overgrowth or ileal disease. The patient is given
250 mg of tetracycline four times daily for 10 days. Tetracycline
reduces the intestinal bacteria in blind loop syndrome. Blind loops
occur when a segment of the intestine is not contiguous with the rest of
the gastrointestinal tract, which necessarily occurs with some surgical
procedures. The loops are subject to bacterial overgrowth that may
lead to malabsorption. If the excretion of radiolabeled vitamin B12
improves after the tetracycline, a malabsorptive syndrome related to
intestinal bacteria is confirmed.


TREATMENT

Treatment is divided into two

 Pharmacological
 Non pharmacological

Non pharmacological

DIET
 Fish
 Meat
 Milk

Pharmacological
 Oral doses may be initiated at 1 to 2 mg daily for 1 to 2 weeks,followed by 1
mg daily,since doses less than 0.5 mg may result in variable absorption.The
1 mg cobalamin tablets are available over the counter.
 Commonly used initial parentral vitamin B 12 regimen consist of 1 mg of
1,000 mcg of cynocobalamin 1M for 1 week to saturate vit B 12 stores in
body.
 In addition to the oral and parentral form,vit B 12 is available in an intranasal
gel formulation.This may be advantageous for patients who are home
bound,have a cognitive impairment.

ADR

 Hyperurecemia
 Hypokalemia
 Thrombocytosis
 Thrombosis
 Sodium water retention
 Oedema

FOLIC ACID DEFICIENCY ANEMIA

Folic acid deficency anemia is due to folic acid deficiency.


  Largely due to its association with excessive alcohol intake and
pregnancy.
 Major causes of folic acid deficiency
includeinadequate,intake,decreased absorption,hyperutilization,drug
induced.
 Folic acid is essential for DNA synthesis.
 Hyperutilization of folic acid may occur.
 Hyperutilization of foli acid may occur when the rate of cellular
division is increased as is seen during pregnancy,hemolytic
anemia,malignancy,chronic inflammatory disorders.
 Drugs that directly inhibit DNA synthesis are-

Nucleic acid antagonist-Zedovudine,Azathioprine,Hydroxy urea

Folate antagonist-Trimethoprim,Methorexate,Sulphasalazine,

Decrese absorption-Phenytoin,Phenobarbitone,Primidone

Drug inhibition-Oral contraceptives,Anticoagulants,Alcohol

PHYSIOLOGICAL IMPORTANCE OF FOLIC ACID

 Folic acid is a type of vitamin,it is the man made form of folate that is found
in supplements and added to fortified foods.
 Folate helps tissues grow and cells work.
 Taking the right amount of folic acid before and during pregnancy helps
prevent certain birth defects.
 Folate also helps to prevent anemia.
 Folic acid also used for other conditions commonly associated with folic
acid deficiency,including ulcerative colitis,liver disease,alcoholism and
kidney dialysis.


 PATHOPHYSIOLOGY
 Folic acid is nessacery for the production of nucleic acids,proteins,amino
acids,purines and hence DNA and RNA.It acts as a methyl donor to form
methyl cobalamin, which is used in the remethylation of homocysteine to
methionine.Because humans are unable to synthesize sufficient foolate to
meet to total daily requirements,they depend on dietary sources.Most folate
in food is present in the polyglutamate form,which must be broken down
into the monoglutamate form prior to absorption in the small intestine.Once
absorbed,dietary folate must be converted to the active form tetrahydro
folate through a cobalamin dependent reaction.In 1997,the u s govt
mandated the fortification of grain products with folic acid in an attempt to
increse the dietary intake of folate by 100 mcg if folate daily per person.This
amount of supplimentation was chosen to decrease the incidence of neural
tube defects without masking vit B12 deficiency.As a result of grain products
fortification,neural tube defect frequency has decreased by 25% to 30%.

Folate is distributed to other tissues primary via enterohepatic

recirculation.The methylated form of folate is reabsorbed from the bile into the
serum.As folate enters the tissue, including erethrocytes,it endure for the remaining
life span of the cell.

LABORATORY INVESTIGATION

 Vit B12 levels are normal

 Homocystine level is incresed
 Decreases occures in the serum folate level(<3ng/ml) within a few
days of dietary folate limitations.
 The RBC folate level (<150ng/ml)also declines and may be a better
indicator of deficiency,as levels remain constant throughout the
lifespan of the erythrocyte.
 If serum or erythrocyte levels are borderline,serum homocystein is
usually increased with a folic acid deficiency.
TREATMENT


  NON PHARMACOLOGICAL
DIET

Fruit,Diary pdts,Liver

 PHARMACOLOGICAL
Usually managed by replacement therapy

The normal daily requirement of folic acid is

apporoximately 100 microgram a day.Despite this,the usual
treatment doses gi ven are 5-15 mg a day.

In the case of pregnancy prophylaxis with folate (350-

500microgrm daily)is now frequently given in
pregnancy ,often in combination with iron,starting before
conception and during the first 12 wks of pregnancy.

In the majority of cases ,1 mg daily is sufficient to replace

stores cxcept in cases of deficiency due to malabsorption in
which case doses up to 5 mg daily may be necessary.

Folic acid supplimentation (800 to1000)prior to conception

and during pregnancy reduces the incidence of neural tube
defects in the general population.

Women who have previously given birth to offspring with

neural tube defects or those with a family history of neural
tube defects should injest 4 mg of folic acid daily.

Finally,it has been suggested that supplimentation with 10

mg of folic acid daily may reduce the incidence of cleft clip.

It is clearly essential that women in their child bearing

years maintain adequate folic acid intake.

ADR

Adverse effects have notbeen reported with folic acid doses

used for replacement therapy.