Pernicious Anemia - ECE

ECE on Pernicious anaemia
Learning objectives
At the end of the session, Phase I MBBS students must be
able to:
• Classify anemia
• Discuss the common causes of pernicious anemia
• Understand the absorption and transport of vitamin B12
• Describe the pathophysiology of pernicious anaemia
• List the signs and symptoms of pernicious anemia
• Discuss the diagnostic approach & treatment of pernicious
anaemia
Pernicious Anemia
• Pernicious means destructive, injurious or
deadly.
• The term pernicious anemia, a relic of the days

when the cause and therapy of this condition
were unknown, is used to describe vitamin B12
deficiency resulting from defective secretion
of intrinsic factor by an atrophic gastric
mucosa.
Introduction to Vitamin B12
• Vit B12 is water soluble with a
key role in normal
functioning of CNS (brain &
spinal cord) & RBCs.
• B12 is also known as Red
vitamin because it exists as a
dark red crystalline
compound.
• Color is due to Cobalt metal
ion.
Synonyms are :-
• Cyanocobalamine
• Anti pernicious anemia factor
&
• Extrinsic factor of castle
HISTORICAL MILESTONE
George Whipple Studies on effect of feeding liver in
anemia started by him.
 In 1934, George Whipple shared
Nobel Prize in Physiology or Medicine with
William P. Murphy and George Minot for discovery of
an effective treatment for pernicious anemia using
liver concentrate, later found to contain a large
amount of vitamin B12.
Sources
• Cobalamin is synthesized solely by
microorganisms.
• Ruminants obtain cobalamin from the foregut,
but the only source for humans is food of
animal origin, e.g. meat, chicken, fish, eggs,
liver and dairy products.
• Strict vegetarians are at risk of developing B12
deficiency.
Sources
Sources
B12 IN LIQUID FORM B12 IN PILL FORM

RDA
• 1-2 μgms/day in adults

• 0.5- 1.5 μgms/day in children
• 3-4 μgms/day in pregnancy & lactation
Forms of Vit. B12
• Cyanocobalamin:- when cyanide is added at R position.
(present in supplements, more stable) Has no physiological
function. Used as oral preparation.
• Hydroxycobalamin:- when OH group is added, natural form,
produced by bacteria, used in supplementation tablets and
injections
• Adenocylcobalamin:- adenosyl is added, active form &
major storage form in liver.
• Methylcobalamin:- methyl group is added, major circulatory
form in blood.
• Ado-12 & methyl B12 are the functional co-enzyme in the
body
ABSORPTION OF VITAMIN B12
Transport of Vitamin B12
• Following absorption by the ileal mucosal

cells, vitamin B12 is carried in the plasma by
various transporting proteins:
• Transcobalamin I
• Transcobalamin II
• Transcobalamin I (TC I) is an alpha-globulin
produced by granulocytes. It functions as a
circulating reserve store of B12. TC I carries mostly
methylcobalamin.
• Transcobalamin II (TC II) is a beta-globulin

formed in the liver and is the dominant carrier of
B12 immediately after absorption. It is the main
agent for rapid transport of B12 to the body cells.
Adenosylcobalamin and methylcobalamin formation
• Once vitamin B12 is absorbed, the body handles
it very efficiently.
• It is stored in the liver, which normally contains
reserves that are sufficient to support bodily
needs for more than 5 years.
• Therefore, the symptoms of pernicious anemia
usually do not appear for years.
• PA begins in middle age or later (usually after
age 40 years).
Etiology of Vit B12 deficiency
Insufficient dietary intake (very rare) -
• Strict vegetarians
Deficient absorption -
• Pernicious anaemia- IF deficiency
• Total or partial gastrectomy
• Prolonged use of PPI or H2 blockers
• Diseases of small intestine
• Fish tapeworm infestation
• Chronic atrophic gastritis
• PA develops as a result of autoimmune
destruction of the acid and pepsin secreting
portion of the gastric mucosa
• Autoantibodies are present in the serum and
gastric juice of most patients with pernicious
anemia.
Three types of antibodies have been
found:
• Parietal canalicular antibodies which bind to the

mucosal parietal cells; Parietal cell antibody is
directed to the membrane H+-K+ ATP pump.
• TYPE 1 / Blocking antibodies which block the
binding of vitamin B12 to intrinsic factor; and
• TYPE 2 / Binding antibodies that react with

intrinsic factor-B12 complex and prevent it from
binding to the ileal receptor.
• Pernicious anemia is sometimes associated
with other autoimmune diseases such as
Addison disease, Graves'disease,
Hashimoto's thyroiditis and vitiligo .
• PA have an increased risk of gastric carcinoma.

Role of vitamin B12
• Vitamin B12 is crucial for DNA synthesis,

methylation, folate metabolism,
erythropoiesis, neurodevelopment & nervous
system function.
Autoimmune gastritis Gastric atrophy
PERNICIOUS
Loss of parietal cells, IF
ANEMIA
Dec Absorption of Dietary B12
PATHOPHYSIO
LOGY Vit B12 deficiency
Atrophic Subacute
Megaloblastic Peripheral
glossitis combined
Anemia neuropathy
degeneration
of spinal cord
Pathogenesis
• When vitamin B12 is deficient, thymidine
synthase function is impaired and DNA
synthesis is interrupted but RNA synthesis
remains unimpaired.
• The inability to synthesize DNA leads to
ineffectual erythropoiesis resulting in excess
hemoglobin and enlarged erythroid
precursors.
• The principal neurologic lesions associated with
vitamin B12 deficiency are demyelination of the
posterior and lateral columns of the spinal cord,
peripheral nerves and brain.
• At the brain it results in dementia, psychotic
depression and paranoid schizophrenia. This has
been termed “megaloblastic madness.”
Findings in Bone Marrow
• Hypercellular
• Intense erythroid hyperplasia with megaloblasts.
• Giant band form and metamyelocyte
• A result of impaired DNA synthesis due to def. in

Folate and/or vitamin B12 (cobalamin).
Clinical Features
• Anaemia symptoms
• Neurological symptoms
• Gastro- intestinal complain
Symptoms of Anemia :
• Weakness, palpitation, fatigue, shortness of breath,
premature graying of hair, jaundice and pallor.
• Severe pallor and slight jaundice combine to

produce a lemon-yellow skin in patient with
megaloblastic anemia.
Neurological symptoms:
• Paraesthesia (numbness and tingling) in the feet and
fingers.
• When it affects the spinal cord it causes spastic

ataxia( stiffness of the muscles with uncoordinated
movement) difficulties in balance and walking & loss of
position sense.
• At the brain it results in dementia, psychotic depression

and schizophrenia. This has been termed “megaloblastic
madness.”
• Gastro- intestinal complains : loss of
appetite, angular stomatitis, glossitis (beefy
red, sore, smooth tongue) and diarrhoea.
Diagnostic approach
SUMMARY OF DIAGNOSTIC FEATURES
1. Moderate to severe megaloblastic anemia

2. Leucopenia with hypersegmented neutrophils
3. Mild to moderate thrombocytopenia
4. Low-normal absolute reticulocyte count
5. Pancytopenia
6. Mild jaundice due to ineffective erythropoiesis
7. Neurologic changes
8. Low levels of serum B12
9. Elevated levels of homocysteine
10. Elevated levels of methylmalonic acid
11. Serum antibodies to intrinsic factor (specific)
and anti parietal cell antibodies in serum
12. Schilling test
13. Bone marrow examination
Note
– In folate def, only HC is elevated .
– In B-12 def, both HC and MMA is elevated.
– Presence of neurological deficits may also indicate B-
12 def.
Treatment
– IM B-12 at 1000 mcg daily for one week, then

1000 mcg weekly for one month, then 1000 mcg
every month for one year – indefinitely.
– No harm in “overtreatment.” Inexpensive, non-
toxic and excess is excreted in urine.
• Response to Treatment
– Reticulocytosis in 3-4 days
– Rise in Hgb concentration within 10 days and
normalization in 8 weeks as well as correction of
MCV.
– Hypersegmented PMN disappear in 10-14 days
CASE STUDY
A 48 year old male with

past medical history of
chronic gastritis presented
with generalized fatigue.
This has been going on for
months. In the past months
he has noted paresthesias
with numbness in his feet.
A CBC demonstrates the
findings shown.
Thank you

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ECE on Pernicious anaemia

• The term pernicious anemia, a relic of the days

B12 IN LIQUID FORM B12 IN PILL FORM

• 1-2 μgms/day in adults

• Following absorption by the ileal mucosal

• Transcobalamin II (TC II) is a beta-globulin

• Parietal canalicular antibodies which bind to the

• TYPE 2 / Binding antibodies that react with

• PA have an increased risk of gastric carcinoma.

• Vitamin B12 is crucial for DNA synthesis,

• Intense erythroid hyperplasia with megaloblasts.

• Giant band form and metamyelocyte

• A result of impaired DNA synthesis due to def. in

• Severe pallor and slight jaundice combine to

• When it affects the spinal cord it causes spastic

• At the brain it results in dementia, psychotic depression

1. Moderate to severe megaloblastic anemia

– IM B-12 at 1000 mcg daily for one week, then

A 48 year old male with

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